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Version 1. F1000Res. 2017; 6: 1121.
Published online 2017 July 12. doi:  10.12688/f1000research.11820.1
PMCID: PMC5510019

Progress toward an integrated understanding of Parkinson’s disease

Maxime W.C. Rousseaux, Writing – Original Draft Preparation, Writing – Review & Editing,1,2 Joshua M. Shulman, Writing – Original Draft Preparation, Writing – Review & Editing,1,2,3,4 and Joseph Jankovic, Writing – Original Draft Preparation, Writing – Review & Editinga,3


Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting over 10 million individuals worldwide. While numerous effective symptomatic treatments are currently available, no curative or disease-modifying therapies exist. An integrated, comprehensive understanding of PD pathogenic mechanisms will likely address this unmet clinical need. Here, we highlight recent progress in PD research with an emphasis on promising translational findings, including (i) advances in our understanding of disease susceptibility, (ii) improved knowledge of cellular dysfunction, and (iii) insights into mechanisms of spread and propagation of PD pathology. We emphasize connections between these previously disparate strands of PD research and the development of an emerging systems-level understanding that will enable the next generation of PD therapeutics.

Keywords: Parkinson's disease, PD, neurodegenerative disorders, α-Synuclein, Parkinson's disease genetics


Parkinson’s disease (PD) is the most common movement disorder, affecting 2–3% of individuals over the age of 65 1. It is clinically characterized by a core set of motor manifestations, including tremor, slow movement (bradykinesia), increased muscle tone (rigidity), and gait and postural impairment as well as a variety of other motor and non-motor features, including cognitive impairment, depression, pain and other sensory symptoms, autonomic dysfunction, and others 2. PD is characterized pathologically by the loss of predominantly dopaminergic neurons, associated with intracellular, insoluble α-synuclein (α-Syn) aggregates, largely localized to cytoplasmic inclusions termed Lewy bodies and within neuronal processes termed Lewy neurites. Whereas current treatments can ameliorate the cardinal motor symptoms, no disease-modifying therapies exist 3. A large body of research has therefore focused on understanding the biological mechanisms that underlie disease onset and progression, with the goal of developing effective pathogenesis-targeted, disease-modifying therapies.

As this year marks the 200-year anniversary of the recognition of PD by James Parkinson 4, we also celebrate the remarkable progress in understanding PD etiology and pathogenesis 5. Here, we review recent advances in the study of the genetics, cell biology, and pathology of PD, highlighting emerging areas of overlap. Where these areas were previously studied in isolation, results from these disparate strands of research are beginning to converge, providing a more unified understanding of PD pathogenesis. We argue that this integrative approach to PD, in which seemingly disconnected results are re-examined as components of a cohesive whole, is also creating exciting opportunities for clinical applications.

Functional genomics and the promise of personalized medicine

Although only a small minority of patients with PD have thus far been found to have responsible pathogenic gene mutations, genetic discoveries have nevertheless been a driving force in the elucidation of PD mechanisms. Following on the early success from studies of rare families with Mendelian forms of PD, more than 20 PD genes and variants have now been implicated, including from large-scale genome-wide association studies (GWAS) and, more recently, whole exome sequencing (WES) studies in population-based cohorts 68. A common challenge with either approach entails definitive confirmation of the responsible genes and elucidation of implicated disease mechanisms. In GWAS, implicated genomic regions often contain several equally plausible gene candidates. Whereas WES studies usually single out specific gene candidates, the implicated alleles may be too rare to definitively confirm a causal link to PD based on currently available sample sizes. Medium- to high-throughput screening assays in cellular or animal models can connect promising candidate genes to PD-relevant biologic mechanisms, prioritizing a subset for further study. For example, Jansen et al. 9 evaluated 27 promising candidate genes with homozygous or compound heterozygous loss-of-function alleles based on WES in 1,148 unrelated young-onset PD cases. Since nearly all of the gene candidates were observed only once in the cohort, the investigators probed each gene for roles in mitochondrial dynamics or α-Syn-mediated toxicity using cellular and fruit fly experimental models. Ultimately, five genes were supported by both functional data and additional human genetic analyses consistent with replication. Beyond accelerating the discovery of novel PD genes, related approaches are also revealing the function of many other established genes/variants, grouping discrete susceptibility loci into common pathways and thereby consolidating our understanding of PD pathogenesis. For example, the recently identified PD gene CHCHD2 may mediate its activity through a mitochondrial pathway like other recessive PD genes (see below) 1012. Moreover, VPS35 and EIF4G1, both implicated in autosomal dominant forms of PD 1317, were recently found to genetically interact with one another and converge on α-Syn toxicity in yeast, worm, and mouse models of synucleinopathy 18.

By contrast, with the sequence-based discovery of rare variant PD risk factors, the susceptibility alleles identified by GWAS 7 usually do not alter protein-coding regions, making functional follow-up more challenging. For example, one of the earliest discovered PD risk polymorphisms at the human MAPT locus may primarily impact alternative mRNA splicing 19, 20. In another recent study, Soldner et al. used human pluripotent cell-derived neurons containing an intronic PD-related variant in the gene encoding α-Syn ( SNCA) 21. The authors found that this common polymorphism, which is present in about half of the population, coincided with a distal enhancer element resulting in an approximately 10% increase in SNCA transcript levels. It was therefore suggested that a mild increase of α-Syn over the course of decades renders individuals susceptible to PD. This is consistent with the findings from rare families with SNCA locus multiplication. In these cases, individuals with SNCA gene mulptiplication present with clinical features typical of PD, including a similar age at onset to sporadic PD 22, 23, whereas individuals with SNCA gene triplication present with a more early onset, aggressive form of PD 24. Thus, SNCA gene dosage may be an integral feature of PD pathogenesis. In the case of the more common SNCA polymorphism, the modest increase in α-Syn protein levels may interact with other genetic risk variants or environmental exposures to cause PD. For example, Goldman et al. found that head injury was significantly associated with increased PD risk, but only in the context of a disease-associated SNCA promoter polymorphism 25.

One of the great hopes for advances in PD genetics is to realize goals for personalized medicine, including improved risk prediction and even targeted therapies. It has long been speculated that much of PD’s clinical heterogeneity may be genetically encoded 26, 27. For example, besides their potent impact on risk of PD 28, GBA mutations have been reported by several groups to cause an earlier age-at-onset, more rapid progression, and an increased risk of cognitive impairment and dementia in carriers 2934. Moreover, additional studies have looked at the effect of allelic heterogeneity on modifying PD clinical presentations 3537. In the future, it may be important to couple such studies examining the clinical impact of selected allelic variants with experimental investigations to define functional consequences in well-defined cellular or animal models. Moreover, once characterized, these models can serve as a platform for testing putative “personalized” treatments 3842. For example, Sanofi Genzyme is currently supporting a study (MOVES-PD) of GZ/SAR402671, a glucosylceramide synthase inhibitor, in PD patients carrying a GBA gene mutation (, NCT02906020). Another study (AiM-PD) is examining the effects of oral Ambroxol, a glucocerebrosidase-modulating chaperone, in patients with PD (, NCT02941822). Lastly, the use of biomarkers in stratifying clinical populations and understanding the biological underpinning of PD subtypes will be critically important when developing personalized medicine approaches. Specifically, profiling blood and CSF biomarkers may enhance disease subtyping based on clinical manifestations alone. This hypothesis is currently being tested in the Parkinson’s Progression Markers Initiative (PPMI) led by the Michael J. Fox Foundation for Parkinson’s Research 43, 44.

From genes to organelles and cellular homeostasis

The maintenance and function of cellular organelles, including mitochondria and lysosomes, are critical for functional neuronal integrity 4547. Interestingly, several previously identified PD genes such as PARK2, PARK6, and PARK7 (encoding Parkin, PTEN-induced putative kinase 1 [PINK1], and DJ-1, respectively) have been linked to mitochondrial function 4854. Since their initial discovery, a large body of work has elucidated a cellular pathway through which dysfunctional mitochondria can be recycled by way of autophagy or, more specifically, “mitophagy” 5559. Damaged mitochondria promote the phosphorylation of ubiquitin and Parkin by PINK1 and are subsequently degraded by the autophagosomal system 5962. Additionally, studies of these genes have provided insight into their mitochondrial functions in healthy and diseased contexts. For example, a recent study suggests that Parkin acts as an endogenous buffer for mitochondrial stress and its loss sensitizes dopaminergic neurons to mitochondrial mutations over time 63, 64. In addition, using a fly model, Vos and colleagues 65 discovered a new pathway that could suppress the motor and biochemical abnormalities caused by PINK1 loss of function. Specifically, PINK1 genetically interacts with the enzyme responsible for the conversion of vitamin K1 into vitamin K2 65. Remarkably, supplementation of vitamin K2 could reverse PINK1 mutant phenotypes, suggesting a potential therapeutic approach. However, patient selection will be critical for potential clinical trials, as PARK6 mutations result in rare, autosomal recessive juvenile parkinsonism 66, and it is uncertain whether a similar functional deficiency in vitamin K2 may apply in the general PD patient population. Identifying the subcellular impact of other PD genes may similarly lead to other targeted therapies.

Beyond discovering the primary targets of genetic abnormalities, it is essential to understand the subsequent cascade of cellular injury, such as how damaged mitochondria impact other cellular constituents, leading to neuronal dysfunction and death. In other words, discrete targets must be understood in the context of a cohesive, dynamic system. One example comes from recent studies that strongly implicate defects in the vesicular trafficking system 67, which mediates cellular secretion and endocytosis as well as vesicle docking and fusion and is critically important for synaptic transmission, lysosomal degradation, and autophagy. Several PD genes, including VPS35, LRRK2, RAB7L1, GBA, and SNCA, have functions that converge on the vesicular trafficking system 6770. Leucine-rich repeat kinase 2 (LRRK2) and Rab-7-like protein 1 (RAB7L1), for example, act coordinately to regulate endolysosomal protein sorting via Rab GTPases, and several studies also support a key role for the cargo-shuttling retromer protein vacuolar protein sorting 35 (VPS35) 7173. In fact, the retromer is implicated as a critical downstream effector whose dysfunction may lead to neuronal toxicity and death 74. Importantly, VPS35 may also play a role in mitophagy, perhaps via trafficking of mitochondria-derived vesicles to lysosomes 75. The dense interconnections between PD genes and other regulators of vesicular trafficking were highlighted by recent work that combined an α-Syn protein–protein interaction network with suppressor-enhancer screening in yeast 76, 77. Based on these and other findings, chemical modulators of autophagy and/or the retromer, such as rapamycin (or similar “rapalogues”) 78, 79 and R55 80, 81, respectively, may be promising therapeutic avenues for targeting vesicular sorting defects in PD. However, since these pathways mediate essential functions in most tissues, successful dose titration to achieve selective action in the nervous system while minimizing potentially deleterious off-target effects is one anticipated challenge 82. Nevertheless, these studies illustrate how the emerging, systems-based understanding of PD can highlight vulnerable “nodes” within complex cellular networks, creating promising therapeutic opportunities.

α-Syn toxicity and propagation: from cells to systems

The centrality of α-Syn in PD pathogenesis was established nearly two decades ago with the dual finding that (i) this protein is the principal constituent of the hallmark Lewy body pathology 83 and (ii) SNCA gene mutations cause familial forms of PD 84. Since then, α-Syn genomic locus multiplication 2224 or promoter polymorphisms that increase protein expression 21 have also been confirmed as causal factors. Thus, intensive investigation has probed the relationship between α-Syn with PD pathogenesis. α-Syn was first described as a member of the synuclein family, which is associated with the synapse and the nucleus 85. While studies on the physiological function of α-Syn suggest that it may play a role in synaptic transmission 86 and aid in curving cellular membranes 87, less is known regarding the mechanism(s) through which its gain-of-function causes neurodegeneration. Thus, one aspect of α-Syn research has focused on understanding how this protein causes toxicity within the cell. Studies in both animal models and human tissue have highlighted a role for α-Syn at the outer mitochondrial membrane 88, 89, the nucleus 9092, and the synapse 93, 94 as putative toxic mechanisms. Moreover, mechanisms involving proteostasis 95, 96 and lysosomal dysfunction 45 that collectively lead to increased α-Syn levels are also tantalizing.

Given the direct relationship between α-Syn abundance and its role in PD pathogenesis and propagation, immunotherapy against α-Syn has emerged as one of the most promising therapeutic approaches for PD 97, 98. Results from ongoing and future immunotherapeutic trials by Prothena/Roche, Biogen, AFFiRiS, and other biotech companies will provide information on whether aggregated α-Syn is an important therapeutic target 99. Nevertheless, caution is warranted given previous negative outcomes from immunotherapeutic trials of other neurodegenerative diseases, such as Alzheimer’s disease, characterized by protein aggregation (proteinopathies) 100.

Another avenue for therapeutic intervention that is actively being investigated is based on the observation that hyperactivity of the non-receptor tyrosine kinase c-Abl contributes to α-Syn phosphorylation, accumulation, and neurodegeneration 101. This has led to preliminary investigation of Nilotinib, a c-Abl inhibitor previously approved for the treatment of chronic myeloid leukemia, as a potential therapeutic agent for PD 102. Further studies, however, are needed before this potent drug can be recommended as a symptomatic or disease-modifying therapy for PD 103. A single-center trial at Georgetown University (, NCT02954978) and a multicenter trial (NILO-PD) (, NCT02281474), sponsored by the Michael J. Fox Foundation for Parkinson’s Research and the Parkinson Study Group, are currently under way.

Since the seminal observation by Braak and colleagues that most idiopathic PD cases fit a relatively predictable, caudal to rostral pathologic staging progression 104, there has been great interest in understanding the mechanism by which α-Syn pathology may spread from the peripheral organs (e.g. the enteric or pericardial tissue) via the vagus nerve to the lower brainstem and eventually involve the neocortex. The intriguing possibility that α-Syn pathology can spread from cell to cell 105107 was suggested by observations of Lewy-like pathology in engrafted neurons from PD patients receiving fetal dopaminergic cell transplants 108, 109. First studies indicated that aggregates of α-Syn could enter cells that express transgenic α-Syn and seed the formation of new aggregates 110, 111. More recently, research findings have indicated that even synthetic, wild-type forms of α-Syn, if improperly folded and injected in the mouse brain, can induce the misfolding of otherwise normal endogenous α-Syn, thereby amplifying and propagating pathological forms 112114, properties consistent with those of prions (infectious proteinaceous agents) 115. It appears that α-Syn can adopt a variety of different misfolded/aggregated oligomeric conformations that correspond to distinct profiles of toxicity in experimental assays 116, 117. These findings raise the intriguing, though yet unproven, hypothesis that certain α-Syn “strains” may contribute to clinical and pathologic heterogeneity among PD and other synucleinopathies. Interestingly, Mao et al. 118 recently identified lymphocyte-activation gene 3 (LAG3) as a candidate receptor for α-Syn oligomeric “seeds”, and genetic manipulation of LAG3 in cells and mouse models altered pathologic progression. These findings raise the possibility of diagnostic and therapeutic advance based on the detection of α-Syn strains in patient populations as well as potential pharmacologic blockade of propagation 118. It is also possible that neuroanatomic variation among key co-factors or receptors for α-Syn seeding or spread might contribute to the selective vulnerability of specific neuronal subpopulations in PD. Despite remarkable recent progress, the clinical relevance of α-Syn seeding and propagation (if any) remains to be fully understood 105, 119, 120. For example, autopsies from some PD patients receiving fetal grafts were devoid of pathology two decades following transplantation 121, 122. Another recent study found that individuals receiving human growth hormone derived from human cadavers were at no greater risk of developing PD 123. The extent of pathological spread of α-Syn does not always follow a defined trans-synaptic pattern nor does the brain areas it affects fully correlate with clinical measures 105. Thus, a continued investigation into the mechanism through which α-Syn pathological assemblies form and how these are tied to toxicity is warranted.

Gastrointestinal dysmotility is a common early complaint in PD patients 124, 125, and the enteric nervous system has been implicated as an early target of α-Syn pathology 104, 126. Along with the growing interest in immunologic and inflammatory disease mechanisms, the gut microbiome has recently come under investigation in studies of both PD patients 127130 and animal models 131. Sampson and colleagues 131 found that α-Syn transgenic mice living in a germ-free environment were less vulnerable to neurodegeneration, but when the mice were inoculated with fecal bacteria taken from patients with PD their motor function deteriorated. While this study suggests the possibility that the gut microbiome may influence PD manifestations, it will be important to define the specific microbial contributors to the disease as well as recapitulate these findings in other disease models before moving forward into humans 132. Beyond its potential role in disease modulation, the gastrointestinal tract might even be a trigger point for disease based on the findings of early enteric nervous system α-Syn pathology in some pathologic series 104. Long before the current excitement concerning α-Syn propagation, Braak et al. speculated about a possible gastrointestinal pathogen (or other enteric exposure) as an initiating event, followed by pathologic spread via the vagus nerve to its medullary dorsal motor nucleus where PD changes first appear in the brainstem 104, 126, 133. Following up on this provocative hypothesis, investigators recently found that subjects undergoing vagotomy (transection of the vagal nerve for the treatment of peptic ulcer disease) are at a modest but significantly reduced risk of PD 134, 135. While intriguing, the finding requires further confirmation, and animal model studies will be essential to definitively prove that the mechanism of protection is indeed based on the disruption of spread from the enteric to the central nervous system.


Recent advances have clearly enhanced our knowledge of the fundamental processes underlying PD pathogenesis. As connections are recognized among the disparate domains of PD inquiry, the broader patterns begin to emerge. As discussed above, we now recognize the cellular targets of many PD genes, such as how PARKIN and GBA regulate mitochondrial or lysosomal function, respectively. Additionally, the field has made progress toward understanding how dynamic interactions between such organelles impact overall cellular health, as in mitophagy. Lastly, studies of α-Syn illustrate the convergence of classical histopathologic analysis of PD with genetic investigations, and more recent investigations demonstrate how synucleinopathy not only impacts single cells or tissues but also may propagate throughout the nervous system. In sum, we are rapidly making progress toward a more cohesive model of PD pathogenesis, and this systems-level understanding is likely to accelerate therapeutic inroads. With the broad outlines of the “PD puzzle” now apparent ( Figure 1), we predict that new insights can be more rapidly integrated within this framework. For example, forthcoming discoveries of new genetic risk loci can be understood within the context of known functional pathways within both neurons and other cell types, such as astrocytes or microglia. An integrated understanding of PD will also enable more effective multi- and inter-disciplinary collaboration among scientists and clinicians, driving next-generation therapeutic trials targeting disease mechanisms and fulfilling the promise of personalized medicine. Advances in understanding the cellular mechanism underlying PD-related neurodegeneration will undoubtedly lead to better symptomatic and novel pathogenesis-targeted, disease-modifying therapies 136.

Figure 1.
Putting the Parkinson’s disease (PD) puzzle together.


α-Syn, α-synuclein; GWAS, genome-wide association study; LAG3, lymphocyte-activation gene 3; PD, Parkinson’s disease; PINK1, PTEN-induced putative kinase 1; VPS35, vacuolar protein sorting 35; WES, whole exome sequencing.


[version 1; referees: 2 approved]

Funding Statement

Maxime W.C. Rousseaux is supported in part by Grant No. PF-JFA-1762 from the Parkinson’s Disease Foundation. Joshua M. Shulman is supported by the Huffington Foundation, the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, and a Career Award for Medical Scientists from the Burroughs Wellcome Fund. Joseph Jankovic has received research and/or educational support from the Michael J. Fox Foundation for Parkinson’s Research, Parkinson’s Foundation, the Parkinson Study Group, Prothena Biosciences Inc, and Teva Pharmaceutical Industries Ltd.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Editorial Note on the Review Process

F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions (any comments will already have been addressed in the published version).

The referees who approved this article are:

  • David G Standaert, , Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
    No competing interests were disclosed.
  • Roger A Barker, University of Cambridge, Cambridge, UK
    No competing interests were disclosed.


1. Poewe W, Seppi K, Tanner CM, et al. : Parkinson disease. Nat Rev Dis Primers. 2017;3:17013. 10.1038/nrdp.2017.13 [PubMed] [Cross Ref] F1000 Recommendation
2. Postuma RB, Berg D, Stern M, et al. : MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30(12):1591–601. 10.1002/mds.26424 [PubMed] [Cross Ref]
3. Lotia M, Jankovic J.: New and emerging medical therapies in Parkinson’s disease. Expert Opin Pharmacother. 2016;17(7):895–909. 10.1517/14656566.2016.1149163 [PubMed] [Cross Ref]
4. Parkinson J.: An essay on the shaking palsy. 1817. J Neuropsychiatry Clin Neurosci. 2002;14(2):223–36; discussion 222. 10.1176/jnp.14.2.223 [PubMed] [Cross Ref]
5. Jankovic J.: Movement disorders in 2016: progress in Parkinson disease and other movement disorders. Nat Rev Neurol. 2017;13(2):76–8. 10.1038/nrneurol.2016.204 [PubMed] [Cross Ref]
6. Farlow JL, Robak LA, Hetrick K, et al. : Whole-exome sequencing in familial Parkinson disease. JAMA Neurol. 2016;73(1):68–75. 10.1001/jamaneurol.2015.3266 [PMC free article] [PubMed] [Cross Ref]
7. Nalls MA, Pankratz N, Lill CM, et al. : Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet. 2014;46(9):989–93. 10.1038/ng.3043 [PMC free article] [PubMed] [Cross Ref]
8. Lill CM.: Genetics of Parkinson’s disease. Mol Cell Probes. 2016;30(6):386–96. 10.1016/j.mcp.2016.11.001 [PubMed] [Cross Ref]
9. Jansen IE, Ye H, Heetveld S, et al. : Discovery and functional prioritization of Parkinson’s disease candidate genes from large-scale whole exome sequencing. Genome Biol. 2017;18(1):22. 10.1186/s13059-017-1147-9 [PMC free article] [PubMed] [Cross Ref]
10. Funayama M, Ohe K, Amo T, et al. : CHCHD2 mutations in autosomal dominant late-onset Parkinson’s disease: a genome-wide linkage and sequencing study. Lancet Neurol. 2015;14(3):274–82. 10.1016/S1474-4422(14)70266-2 [PubMed] [Cross Ref] F1000 Recommendation
11. Singleton A.: A new gene for Parkinson’s disease: should we care? Lancet Neurol. 2015;14(3):238–9. 10.1016/S1474-4422(14)70270-4 [PubMed] [Cross Ref]
12. Ogaki K, Koga S, Heckman MG, et al. : Mitochondrial targeting sequence variants of the CHCHD2 gene are a risk for Lewy body disorders. Neurology. 2015;85(23):2016–25. 10.1212/WNL.0000000000002170 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
13. Deng H, Gao K, Jankovic J.: The VPS35 gene and Parkinson’s disease. Mov Disord. 2013;28(5):569–75. 10.1002/mds.25430 [PubMed] [Cross Ref]
14. Vilariño-Güell C, Wider C, Ross OA, et al. : VPS35 mutations in Parkinson disease. Am J Hum Genet. 2011;89(1):162–7. 10.1016/j.ajhg.2011.06.001 [PubMed] [Cross Ref] F1000 Recommendation
15. Zimprich A, Benet-Pagès A, Struhal W, et al. : A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am J Hum Genet. 2011;89(1):168–75. 10.1016/j.ajhg.2011.06.008 [PubMed] [Cross Ref] F1000 Recommendation
16. Deng H, Wu Y, Jankovic J.: The EIF4G1 gene and Parkinson’s disease. Acta Neurol Scand. 2015;132(2):73–8. 10.1111/ane.12397 [PubMed] [Cross Ref]
17. Chartier-Harlin MC, Dachsel JC, Vilariño-Güell C, et al. : Translation initiator EIF4G1 mutations in familial Parkinson disease. Am J Hum Genet. 2011;89(3):398–406. 10.1016/j.ajhg.2011.08.009 [PubMed] [Cross Ref]
18. Dhungel N, Eleuteri S, Li LB, et al. : Parkinson’s disease genes VPS35 and EIF4G1 interact genetically and converge on α-synuclein. Neuron. 2015;85(1):76–87. 10.1016/j.neuron.2014.11.027 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
19. Trabzuni D, Wray S, Vandrovcova J, et al. : MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies. Hum Mol Genet. 2012;21(18):4094–103. 10.1093/hmg/dds238 [PMC free article] [PubMed] [Cross Ref]
20. Valenca GT, Srivastava GP, Oliveira-Filho J, et al. : The role of MAPT haplotype H2 and isoform 1N/4R in parkinsonism of older adults. PLoS One. 2016;11(7):e0157452. 10.1371/journal.pone.0157452 [PMC free article] [PubMed] [Cross Ref]
21. Soldner F, Stelzer Y, Shivalila CS, et al. : Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression. Nature. 2016;533(7601):95–9. 10.1038/nature17939 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
22. Chartier-Harlin MC, Kachergus J, Roumier C, et al. : Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet. 2004;364(9440):1167–9. 10.1016/S0140-6736(04)17103-1 [PubMed] [Cross Ref]
23. Ibáñez P, Bonnet AM, Débarges B, et al. : Causal relation between alpha-synuclein gene duplication and familial Parkinson’s disease. Lancet. 2004;364(9440):1169–71. 10.1016/S0140-6736(04)17104-3 [PubMed] [Cross Ref]
24. Singleton AB, Farrer M, Johnson J, et al. : Alpha-synuclein locus triplication causes Parkinson’s disease. Science. 2003;302(5646):841. 10.1126/science.1090278 [PubMed] [Cross Ref] F1000 Recommendation
25. Goldman SM, Kamel F, Ross GW, et al. : Head injury, α-synuclein Rep1, and Parkinson’s disease. Ann Neurol. 2012;71(1):40–8. 10.1002/ana.22499 [PMC free article] [PubMed] [Cross Ref]
26. Thenganatt MA, Jankovic J.: Parkinson disease subtypes. JAMA Neurol. 2014;71(4):499–504. 10.1001/jamaneurol.2013.6233 [PubMed] [Cross Ref]
27. Nussbaum RL, Polymeropoulos MH.: Genetics of Parkinson’s disease. Hum Mol Genet. 1997;6(10):1687–91. 10.1093/hmg/6.10.1687 [PubMed] [Cross Ref]
28. Sidransky E, Nalls MA, Aasly JO, et al. : Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med. 2009;361(17):1651–61. 10.1056/NEJMoa0901281 [PMC free article] [PubMed] [Cross Ref]
29. Migdalska-Richards A, Schapira AH.: The relationship between glucocerebrosidase mutations and Parkinson disease. J Neurochem. 2016;139(Suppl 1):77–90. 10.1111/jnc.13385 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
30. Blanz J, Saftig P.: Parkinson’s disease: acid-glucocerebrosidase activity and alpha-synuclein clearance. J Neurochem. 2016;139(Suppl 1):198–215. 10.1111/jnc.13517 [PubMed] [Cross Ref] F1000 Recommendation
31. Brockmann K, Srulijes K, Pflederer S, et al. : GBA-associated Parkinson’s disease: reduced survival and more rapid progression in a prospective longitudinal study. Mov Disord. 2015;30(3):407–11. 10.1002/mds.26071 [PubMed] [Cross Ref] F1000 Recommendation
32. Clark LN, Ross BM, Wang Y, et al. : Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology. 2007;69(12):1270–7. 10.1212/01.wnl.0000276989.17578.02 [PMC free article] [PubMed] [Cross Ref]
33. Davis MY, Johnson CO, Leverenz JB, et al. : Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in Parkinson disease. JAMA Neurol. 2016;73(10):1217–24. 10.1001/jamaneurol.2016.2245 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
34. Winder-Rhodes SE, Evans JR, Ban M, et al. : Glucocerebrosidase mutations influence the natural history of Parkinson’s disease in a community-based incident cohort. Brain. 2013;136(Pt 2):392–9. 10.1093/brain/aws318 [PubMed] [Cross Ref] F1000 Recommendation
35. Nalls MA, McLean CY, Rick J, et al. : Diagnosis of Parkinson’s disease on the basis of clinical and genetic classification: a population-based modelling study. Lancet Neurol. 2015;14(10):1002–9. 10.1016/S1474-4422(15)00178-7 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
36. Pihlstrøm L, Morset KR, Grimstad E, et al. : A cumulative genetic risk score predicts progression in Parkinson’s disease. Mov Disord. 2016;31(4):487–90. 10.1002/mds.26505 [PubMed] [Cross Ref]
37. Mata IF, Leverenz JB, Weintraub D, et al. : GBA variants are associated with a distinct pattern of cognitive deficits in Parkinson’s disease. Mov Disord. 2016;31(1):95–102. 10.1002/mds.26359 [PMC free article] [PubMed] [Cross Ref]
38. Migdalska-Richards A, Daly L, Bezard E, et al. : Ambroxol effects in glucocerebrosidase and α-synuclein transgenic mice. Ann Neurol. 2016;80(5):766–75. 10.1002/ana.24790 [PMC free article] [PubMed] [Cross Ref]
39. Ishay Y, Zimran A, Szer J, et al. : Combined beta-glucosylceramide and ambroxol hydrochloride in patients with Gaucher related Parkinson disease: from clinical observations to drug development. Blood Cells Mol Dis. 2016; pii: S1079-9796(16)30229-7. 10.1016/j.bcmd.2016.10.028 [PubMed] [Cross Ref]
40. Migdalska-Richards A, Ko WKD, Li Q, et al. : Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate. Synapse. 2017;71(7). 10.1002/syn.21967 [PMC free article] [PubMed] [Cross Ref]
41. Wang G, McCain ML, Yang L, et al. : Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat Med. 2014;20(6):616–23. 10.1038/nm.3545 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
42. Zhang YS, Aleman J, Shin SR, et al. : Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors. Proc Natl Acad Sci U S A. 2017;114(12):E2293–E2302. 10.1073/pnas.1612906114 [PubMed] [Cross Ref]
43. Espay AJ, Schwarzschild MA, Tanner CM, et al. : Biomarker-driven phenotyping in Parkinson’s disease: a translational missing link in disease-modifying clinical trials. Mov Disord. 2017;32(3):319–24. 10.1002/mds.26913 [PubMed] [Cross Ref]
44. Parkinson Progression Marker Initiative: The Parkinson Progression Marker Initiative (PPMI). Prog Neurobiol. 2011;95(4):629–35. 10.1016/j.pneurobio.2011.09.005 [PubMed] [Cross Ref]
45. Manzoni C, Lewis PA.: Dysfunction of the autophagy/lysosomal degradation pathway is a shared feature of the genetic synucleinopathies. FASEB J. 2013;27(9):3424–9. 10.1096/fj.12-223842 [PMC free article] [PubMed] [Cross Ref]
46. Schon EA, Manfredi G.: Neuronal degeneration and mitochondrial dysfunction. J Clin Invest. 2003;111(3):303–12. 10.1172/JCI17741 [PMC free article] [PubMed] [Cross Ref]
47. Van Laar VS, Berman SB.: The interplay of neuronal mitochondrial dynamics and bioenergetics: implications for Parkinson’s disease. Neurobiol Dis. 2013;51:43–55. 10.1016/j.nbd.2012.05.015 [PMC free article] [PubMed] [Cross Ref]
48. Haelterman NA, Yoon WH, Sandoval H, et al. : A mitocentric view of Parkinson’s disease. Annu Rev Neurosci. 2014;37:137–59. 10.1146/annurev-neuro-071013-014317 [PMC free article] [PubMed] [Cross Ref]
49. Irrcher I, Aleyasin H, Seifert EL, et al. : Loss of the Parkinson’s disease-linked gene DJ-1 perturbs mitochondrial dynamics. Hum Mol Genet. 2010;19(19):3734–46. 10.1093/hmg/ddq288 [PubMed] [Cross Ref]
50. Park J, Lee SB, Lee S, et al. : Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature. 2006;441(7097):1157–61. 10.1038/nature04788 [PubMed] [Cross Ref] F1000 Recommendation
51. Clark IE, Dodson MW, Jiang C, et al. : Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature. 2006;441(7097):1162–6. 10.1038/nature04779 [PubMed] [Cross Ref] F1000 Recommendation
52. Yang Y, Gehrke S, Imai Y, et al. : Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila pink1 is rescued by parkin. Proc Natl Acad Sci U S A. 2006;103(28):10793–8. 10.1073/pnas.0602493103 [PubMed] [Cross Ref]
53. Canet-Avilés RM, Wilson MA, Miller DW, et al. : The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci U S A. 2004;101(24):9103–8. 10.1073/pnas.0402959101 [PubMed] [Cross Ref]
54. Andres-Mateos E, Perier C, Zhang L, et al. : DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc Natl Acad Sci U S A. 2007;104(37):14807–12. 10.1073/pnas.0703219104 [PubMed] [Cross Ref]
55. Kinghorn KJ, Asghari AM, Castillo-Quan JI.: The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson’s disease. Neural Regen Res. 2017;12(3):380–4. 10.4103/1673-5374.202934 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
56. Rahman MA, Rhim H.: Therapeutic implication of autophagy in neurodegenerative diseases. BMB Rep. 2017; pii: 3831. [PubMed]
57. Youle RJ, Narendra DP.: Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011;12(1):9–14. 10.1038/nrm3028 [PMC free article] [PubMed] [Cross Ref]
58. Narendra DP, Jin SM, Tanaka A, et al. : PINK1 is selectively stabilized on impaired mitochondria to activate parkin. PLoS Biol. 2010;8(1):e1000298. 10.1371/journal.pbio.1000298 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
59. Lazarou M, Sliter DA, Kane LA, et al. : The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015;524(7565):309–14. 10.1038/nature14893 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
60. Kane LA, Lazarou M, Fogel AI, et al. : PINK1 phosphorylates ubiquitin to activate parkin E3 ubiquitin ligase activity. J Cell Biol. 2014;205(2):143–53. 10.1083/jcb.201402104 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
61. Kazlauskaite A, Kondapalli C, Gourlay R, et al. : Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser 65. Biochem J. 2014;460(1):127–39. 10.1042/BJ20140334 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
62. Koyano F, Okatsu K, Kosako H, et al. : Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature. 2014;510(7503):162–6. 10.1038/nature13392 [PubMed] [Cross Ref] F1000 Recommendation
63. Pickrell AM, Youle RJ.: The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron. 2015;85(2):257–73. 10.1016/j.neuron.2014.12.007 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
64. Pickrell AM, Huang CH, Kennedy SR, et al. : Endogenous parkin preserves dopaminergic substantia nigral neurons following mitochondrial DNA mutagenic stress. Neuron. 2015;87(2):371–81. 10.1016/j.neuron.2015.06.034 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
65. Vos M, Esposito G, Edirisinghe JN, et al. : Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency. Science. 2012;336(6086):1306–10. 10.1126/science.1218632 [PubMed] [Cross Ref] F1000 Recommendation
66. Valente EM, Abou-Sleiman PM, Caputo V, et al. : Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science. 2004;304(5674):1158–60. 10.1126/science.1096284 [PubMed] [Cross Ref] F1000 Recommendation
67. Abeliovich A, Gitler AD.: Defects in trafficking bridge Parkinson’s disease pathology and genetics. Nature. 2016;539(7628):207–16. 10.1038/nature20414 [PubMed] [Cross Ref] F1000 Recommendation
68. Wang S, Bellen HJ.: The retromer complex in development and disease. Development. 2015;142(14):2392–6. 10.1242/dev.123737 [PubMed] [Cross Ref]
69. McLelland G, Soubannier V, Chen CX, et al. : Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control. EMBO J. 2014;33(4):282–95. 10.1002/embj.201385902 [PubMed] [Cross Ref] F1000 Recommendation
70. Lashuel HA, Hirling H.: Rescuing defective vesicular trafficking protects against alpha-synuclein toxicity in cellular and animal models of Parkinson’s disease. ACS Chem Biol. 2006;1(7):420–4. 10.1021/cb600331e [PubMed] [Cross Ref]
71. MacLeod DA, Rhinn H, Kuwahara T, et al. : RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk. Neuron. 2013;77(3):425–39. 10.1016/j.neuron.2012.11.033 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
72. Steger M, Tonelli F, Ito G, et al. : Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. eLife. 2016;5: pii: e12813. 10.7554/eLife.12813 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
73. Beilina A, Rudenko IN, Kaganovich A, et al. : Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. Proc Natl Acad Sci U S A. 2014;111(7):2626–31. 10.1073/pnas.1318306111 [PubMed] [Cross Ref]
74. Williams ET, Chen X, Moore DJ.: VPS35, the retromer complex and Parkinson’s disease. J Parkinsons Dis. 2017;7(2):219–33. 10.3233/JPD-161020 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
75. Wang W, Wang X, Fujioka H, et al. : Parkinson’s disease-associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes. Nat Med. 2016;22(1):54–63. 10.1038/nm.3983 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
76. Khurana V, Peng J, Chung CY, et al. : Genome-scale networks link neurodegenerative disease genes to α-synuclein through specific molecular pathways. Cell Syst. 2017;4(2):157–170.e14. 10.1016/j.cels.2016.12.011 [PubMed] [Cross Ref] F1000 Recommendation
77. Chung CY, Khurana V, Yi S, et al. : In situ peroxidase labeling and mass-spectrometry connects alpha-synuclein directly to endocytic trafficking and mRNA metabolism in neurons. Cell Syst. 2017;4(2):242–250.e4. 10.1016/j.cels.2017.01.002 [PubMed] [Cross Ref] F1000 Recommendation
78. Malagelada C, Jin ZH, Jackson-Lewis V, et al. : Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson’s disease. J Neurosci. 2010;30(3):1166–75. 10.1523/JNEUROSCI.3944-09.2010 [PMC free article] [PubMed] [Cross Ref]
79. Moors TE, Hoozemans JJ, Ingrassia A, et al. : Therapeutic potential of autophagy-enhancing agents in Parkinson’s disease. Mol Neurodegener. 2017;12(1):11. 10.1186/s13024-017-0154-3 [PMC free article] [PubMed] [Cross Ref]
80. Follett J, Bugarcic A, Yang Z, et al. : Parkinson disease-linked Vps35 R524W mutation impairs the endosomal association of retromer and induces α-synuclein aggregation. J Biol Chem. 2016;291(35):18283–98. 10.1074/jbc.M115.703157 [PMC free article] [PubMed] [Cross Ref]
81. Mecozzi VJ, Berman DE, Simoes S, et al. : Pharmacological chaperones stabilize retromer to limit APP processing. Nat Chem Biol. 2014;10(6):443–9. 10.1038/nchembio.1508 [PMC free article] [PubMed] [Cross Ref]
82. Salmon AB.: About-face on the metabolic side effects of rapamycin. Oncotarget. 2015;6(5):2585–6. 10.18632/oncotarget.3354 [PMC free article] [PubMed] [Cross Ref]
83. Spillantini MG, Schmidt ML, Lee VM, et al. : Alpha-synuclein in Lewy bodies. Nature. 1997;388(6645):839–40. 10.1038/42166 [PubMed] [Cross Ref]
84. Polymeropoulos MH, Lavedan C, Leroy E, et al. : Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276(5321):2045–7. 10.1126/science.276.5321.2045 [PubMed] [Cross Ref]
85. Maroteaux L, Campanelli JT, Scheller RH.: Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci. 1988;8(8):2804–15. [PubMed]
86. Wales P, Pinho R, Lázaro DF, et al. : Limelight on alpha-synuclein: pathological and mechanistic implications in neurodegeneration. J Parkinsons Dis. 2013;3(4):415–59. 10.3233/JPD-130216 [PubMed] [Cross Ref]
87. West A, Brummel BE, Braun AR, et al. : Membrane remodeling and mechanics: experiments and simulations of α-synuclein. Biochim Biophys Acta. 2016;1858(7 Pt B):1594–609. 10.1016/j.bbamem.2016.03.012 [PMC free article] [PubMed] [Cross Ref]
88. Guardia-Laguarta C, Area-Gomez E, Schon EA, et al. : Novel subcellular localization for α-synuclein: possible functional consequences. Front Neuroanat. 2015;9:17. 10.3389/fnana.2015.00017 [PMC free article] [PubMed] [Cross Ref]
89. Di Maio R, Barrett PJ, Hoffman EK, et al. : α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Sci Transl Med. 2016;8(342):342ra78. 10.1126/scitranslmed.aaf3634 [PMC free article] [PubMed] [Cross Ref]
90. Kontopoulos E, Parvin JD, Feany MB.: Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum Mol Genet. 2006;15(20):3012–23. 10.1093/hmg/ddl243 [PubMed] [Cross Ref]
91. Rousseaux MW, de Haro M, Lasagna-Reeves CA, et al. : TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau. eLife. 2016;5: pii: e19809. 10.7554/eLife.19809 [PMC free article] [PubMed] [Cross Ref]
92. Surguchov A.: Intracellular dynamics of synucleins: “here, there and everywhere”. Int Rev Cell Mol Biol. 2015;320:103–69. 10.1016/bs.ircmb.2015.07.007 [PubMed] [Cross Ref]
93. Rockenstein E, Nuber S, Overk CR, et al. : Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo. Brain. 2014;137(Pt 5):1496–513. 10.1093/brain/awu057 [PMC free article] [PubMed] [Cross Ref]
94. Garcia-Reitböck P, Anichtchik O, Bellucci A, et al. : SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson’s disease. Brain. 2010;133(Pt 7):2032–44. 10.1093/brain/awq132 [PMC free article] [PubMed] [Cross Ref]
95. Schildknecht S, Gerding HR, Karreman C, et al. : Oxidative and nitrative alpha-synuclein modifications and proteostatic stress: implications for disease mechanisms and interventions in synucleinopathies. J Neurochem. 2013;125(4):491–511. 10.1111/jnc.12226 [PubMed] [Cross Ref]
96. Cook C, Stetler C, Petrucelli L.: Disruption of protein quality control in Parkinson’s disease. Cold Spring Harb Perspect Med. 2012;2(5):a009423. 10.1101/cshperspect.a009423 [PMC free article] [PubMed] [Cross Ref]
97. Valera E, Spencer B, Masliah E.: Immunotherapeutic approaches targeting amyloid-β, α-synuclein, and tau for the treatment of neurodegenerative disorders. Neurotherapeutics. 2016;13(1):179–89. 10.1007/s13311-015-0397-z [PMC free article] [PubMed] [Cross Ref]
98. George S, Brundin P.: Immunotherapy in Parkinson’s disease: micromanaging alpha-synuclein aggregation. J Parkinsons Dis. 2015;5(3):413–24. 10.3233/JPD-150630 [PMC free article] [PubMed] [Cross Ref]
99. Jankovic J, Godman I, Safirstein B, et al. : Results from a phase 1b multiple ascending-dose study of PRX002, an anti-alpha-synuclein monoclonal antibody, in patients with Parkinson’s disease. Neurodegener Dis. 2017;17(suppl 1)(567). [Abstract].
100. Wang Y.: Alzheimer disease: lessons from immunotherapy for Alzheimer disease. Nat Rev Neurol. 2014;10(4):188–9. 10.1038/nrneurol.2014.44 [PubMed] [Cross Ref]
101. Brahmachari S, Ge P, Lee SH, et al. : Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration. J Clin Invest. 2016;126(8):2970–88. 10.1172/JCI85456 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
102. Pagan F, Hebron M, Valadez EH, et al. : Nilotinib effects in Parkinson’s disease and dementia with Lewy bodies. J Parkinsons Dis. 2016;6(3):503–17. 10.3233/JPD-160867 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
103. Robledo I, Jankovic J.: Media hype: patient and scientific perspectives on misleading medical news. Mov Disord. 2017. 10.1002/mds.26993 [PubMed] [Cross Ref]
104. Braak H, Del Tredici K, Rüb U, et al. : Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197–211. 10.1016/S0197-4580(02)00065-9 [PubMed] [Cross Ref]
105. Surmeier DJ, Obeso JA, Halliday GM.: Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci. 2017;18(2):101–13. 10.1038/nrn.2016.178 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
106. Hasegawa M, Nonaka T, Masuda-Suzukake M.: α-Synuclein: experimental pathology. Cold Spring Harb Perspect Med. 2016;6(9): pii: a024273. 10.1101/cshperspect.a024273 [PubMed] [Cross Ref]
107. Luna E, Luk KC.: Bent out of shape: α-synuclein misfolding and the convergence of pathogenic pathways in Parkinson’s disease. FEBS Lett. 2015;589(24 Pt A):3749–59. 10.1016/j.febslet.2015.10.023 [PMC free article] [PubMed] [Cross Ref]
108. Kordower JH, Chu Y, Hauser RA, et al. : Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med. 2008;14(5):504–6. 10.1038/nm1747 [PubMed] [Cross Ref]
109. Li JY, Englund E, Holton JL, et al. : Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med. 2008;14(5):501–3. 10.1038/nm1746 [PubMed] [Cross Ref] F1000 Recommendation
110. Desplats P, Lee HJ, Bae EJ, et al. : Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A. 2009;106(31):13010–5. 10.1073/pnas.0903691106 [PubMed] [Cross Ref] F1000 Recommendation
111. Luk KC, Song C, O'Brien P, et al. : Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A. 2009;106(47):20051–6. 10.1073/pnas.0908005106 [PubMed] [Cross Ref]
112. Volpicelli-Daley LA, Luk KC, Patel TP, et al. : Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011;72(1):57–71. 10.1016/j.neuron.2011.08.033 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
113. Luk KC, Kehm V, Carroll J, et al. : Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science. 2012;338(6109):949–53. 10.1126/science.1227157 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
114. Rey NL, Steiner JA, Maroof N, et al. : Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease. J Exp Med. 2016;213(9):1759–78. 10.1084/jem.20160368 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
115. Brundin P, Ma J, Kordower JH.: How strong is the evidence that Parkinson’s disease is a prion disorder? Curr Opin Neurol. 2016;29(4):459–66. 10.1097/WCO.0000000000000349 [PMC free article] [PubMed] [Cross Ref]
116. Peelaerts W, Bousset L, van der Perren A, et al. : α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature. 2015;522(7556):340–4. 10.1038/nature14547 [PubMed] [Cross Ref] F1000 Recommendation
117. Guo JL, Covell DJ, Daniels JP, et al. : Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell. 2013;154(1):103–17. 10.1016/j.cell.2013.05.057 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
118. Mao X, Ou MT, Karuppagounder SS, et al. : Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016;353(6307): pii: aah3374. 10.1126/science.aah3374 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
119. McCann H, Cartwright H, Halliday GM.: Neuropathology of α-synuclein propagation and braak hypothesis. Mov Disord. 2016;31(2):152–60. 10.1002/mds.26421 [PubMed] [Cross Ref]
120. Hansen C, Li JY.: Beyond α-synuclein transfer: pathology propagation in Parkinson’s disease. Trends Mol Med. 2012;18(5):248–55. 10.1016/j.molmed.2012.03.002 [PubMed] [Cross Ref]
121. Hallett PJ, Cooper O, Sadi D, et al. : Long-term health of dopaminergic neuron transplants in Parkinson’s disease patients. Cell Rep. 2014;7(6):1755–61. 10.1016/j.celrep.2014.05.027 [PMC free article] [PubMed] [Cross Ref]
122. Mendez I, Viñuela A, Astradsson A, et al. : Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years. Nat Med. 2008;14(5):507–9. 10.1038/nm1752 [PMC free article] [PubMed] [Cross Ref]
123. Irwin DJ, Abrams JY, Schonberger LB, et al. : Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol. 2013;70(4):462–8. 10.1001/jamaneurol.2013.1933 [PMC free article] [PubMed] [Cross Ref]
124. Su A, Gandhy R, Barlow C, et al. : A practical review of gastrointestinal manifestations in Parkinson’s disease. Parkinsonism Relat Disord. 2017;39:17–26. 10.1016/j.parkreldis.2017.02.029 [PubMed] [Cross Ref]
125. Postuma RB, Berg D.: Advances in markers of prodromal Parkinson disease. Nat Rev Neurol. 2016;12(11):622–34. 10.1038/nrneurol.2016.152 [PubMed] [Cross Ref]
126. Braak H, Rüb U, Gai WP, et al. : Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm (Vienna). 2003;110(5):517–36. 10.1007/s00702-002-0808-2 [PubMed] [Cross Ref]
127. Hill-Burns EM, Debelius JW, Morton JT, et al. : Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome. Mov Disord. 2017;32(5):739–49. 10.1002/mds.26942 [PubMed] [Cross Ref] F1000 Recommendation
128. Malkki H.: Parkinson disease: could gut microbiota influence severity of Parkinson disease? Nat Rev Neurol. 2017;13(2):66–7. 10.1038/nrneurol.2016.195 [PubMed] [Cross Ref] F1000 Recommendation
129. Keshavarzian A, Green SJ, Engen PA, et al. : Colonic bacterial composition in Parkinson’s disease. Mov Disord. 2015;30(10):1351–60. 10.1002/mds.26307 [PubMed] [Cross Ref] F1000 Recommendation
130. Wood H.: Parkinson disease. Gut reactions--can changes in the intestinal microbiome provide new insights into Parkinson disease? Nat Rev Neurol. 2015;11(2):66. 10.1038/nrneurol.2014.256 [PubMed] [Cross Ref]
131. Sampson TR, Debelius JW, Thron T, et al. : Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell. 2016;167(6):1469–1480.e12. 10.1016/j.cell.2016.11.018 [PubMed] [Cross Ref] F1000 Recommendation
132. Parashar A, Udayabanu M.: Gut microbiota: implications in Parkinson’s disease. Parkinsonism Relat Disord. 2017;38:1–7. 10.1016/j.parkreldis.2017.02.002 [PubMed] [Cross Ref]
133. Braak H, Del Tredici K.: Neuropathological staging of brain pathology in sporadic Parkinson’s disease: separating the wheat from the chaff. J Parkinsons Dis. 2017;7(s1):S73–S87. 10.3233/JPD-179001 [PMC free article] [PubMed] [Cross Ref]
134. Liu B, Fang F, Pedersen NL, et al. : Vagotomy and Parkinson disease: a Swedish register-based matched-cohort study. Neurology. 2017;88(21):1996–2002. 10.1212/WNL.0000000000003961 [PMC free article] [PubMed] [Cross Ref] F1000 Recommendation
135. Svensson E, Horváth-Puhó E, Thomsen RW, et al. : Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol. 2015;78(4):522–9. 10.1002/ana.24448 [PubMed] [Cross Ref] F1000 Recommendation
136. Tarakad A, Jankovic J.: Diagnosis and management of Parkinson’s disease. Semin Neurol. 2017;37(2):118–26. 10.1055/s-0037-1601888 [PubMed] [Cross Ref]

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