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1.  Expression of TMEM106B, the frontotemporal lobar degeneration-associated protein, in normal and diseased human brain 
Background
Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia in individuals under 65 years old and manifests as alterations in behavior, personality, or language secondary to degeneration of the frontal and/or temporal lobes. FTLD-TDP, the largest neuropathological subset of FTLD, is characterized by hyperphosphorylated, ubiquitinated TAR DNA-binding protein 43 (TDP-43) inclusions. Mutations in progranulin (GRN), a neuroprotective growth factor, are one of the most common Mendelian genetic causes of FTLD-TDP. Moreover, a recent genome-wide association study (GWAS) identified multiple SNPs within the uncharacterized gene TMEM106B that significantly associated with FTLD-TDP, suggesting that TMEM106B genotype confers risk for FTLD-TDP. Indeed, TMEM106B expression levels, which correlate with TMEM106B genotype, may play a role in the pathogenesis of disease.
Results
Since little is known about TMEM106B and its expression in human brain, we performed immunohistochemical studies of TMEM106B in postmortem human brain samples from normal individuals, FTLD-TDP individuals with and without GRN mutations, and individuals with other neurodegenerative diseases. We find that TMEM106B protein is cytoplasmically expressed in both histopathologically affected and unaffected areas of the brain by neurons, glia, and endothelial cells/pericytes. Furthermore, we demonstrate that TMEM106B expression may differ among neuronal subtypes. Finally, we show that TMEM106B neuronal expression is significantly more disorganized in FTLD-TDP cases with GRN mutations, compared to normal and disease controls, including FTLD-TDP cases without GRN mutations.
Conclusions
Our data provide an initial neuropathological characterization of the newly discovered FTLD-TDP-associated protein TMEM106B. In addition, we demonstrate that FTLD-TDP cases with GRN mutations exhibit a loss of neuronal TMEM106B subcellular localization, adding to evidence that TMEM106B and progranulin may be pathophysiologically linked in FTLD-TDP.
doi:10.1186/2051-5960-1-36
PMCID: PMC3893524  PMID: 24252750
TMEM106B; Frontotemporal lobar degeneration; Frontotemporal dementia; TDP-43; Progranulin; FTLD-TDP
2.  TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis 
Lancet neurology  2008;7(5):409-416.
SUMMARY
BACKGROUND
TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene (TARDBP) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1).
METHODS
TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identifi ed variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families.
FINDINGS
We identified two variants, p.Gly290Ala and p.Gly298Ser, in TARDBP in two familial ALS kindreds and we observed TDP-43 neuropathology in the CNS tissue available from one family. The variants are considered pathogenic mutations because they co-segregate with disease in both families, are absent in ethnically-matched controls, and are associated with TDP-43 neuropathology in several family members.
INTERPRETATION
The p.Gly290Ala and p.Gly298Ser mutations are located in the glycine-rich domain that regulates gene expression and mediates protein-protein interactions; in particular TDP-43 binds to heterogeneous ribonucleoproteins (hnRNPs) via this domain. We postulate that due to the varied and important cellular functions of TDP-43, these mutations may cause neurodegeneration through both gains and losses of function. The finding of TARDBP mutations implicates TDP-43 as an active mediator of neurodegeneration in a novel class of disorders, TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U.
doi:10.1016/S1474-4422(08)70071-1
PMCID: PMC3546119  PMID: 18396105
3.  TDP-43 Pathology in a Case of Hereditary Spastic Paraplegia with a NIPA1/SPG6 Mutation 
Acta neuropathologica  2012;124(2):285-291.
Mutations in NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome) have been described as a cause of autosomal dominant hereditary spastic paraplegia (HSP) known as SPG6 (spastic paraplegia-6). We present the first neuropathological description of a patient with a NIPA1 mutation, and clinical phenotype of complicated HSP with motor neuron disease-like syndrome and cognitive decline. Postmortem examination revealed degeneration of lateral corticospinal tracts and dorsal columns with motor neuron loss. TDP-43 immunostaining showed widespread spinal cord and cerebral skein-like and round neuronal cytoplasmic inclusions. We ruled out NIPA1 mutations in 419 additional cases of motor neuron disease. These findings suggest that hereditary spastic paraplegia due to NIPA1 mutations could represent a TDP-43 proteinopathy.
doi:10.1007/s00401-012-0947-y
PMCID: PMC3361549  PMID: 22302102
4.  Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration 
Archives of neurology  2011;68(4):488-497.
Objective
To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).
Participants and Design
A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLDTDP cases and all of the GRN− FTLD-TDP cases.
Results
Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P<.001), as was age at death (median, 65.5 vs 69.0 years; P<.001). Concomitant motor neuron disease was much less common in GRN+ FTLDTDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P<.001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.
Conclusion
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
doi:10.1001/archneurol.2011.53
PMCID: PMC3160280  PMID: 21482928
5.  Exome sequencing reveals VCP mutations as a cause of familial ALS 
Neuron  2010;68(5):857-864.
Summary
Using exome sequencing, we identified a p.R191Q amino acid change in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). Mutations in VCP have previously been identified in families with Inclusion Body Myopathy, Paget’s disease and Frontotemporal Dementia (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically-proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ~1–2% of familial ALS, and represent the first evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration.
doi:10.1016/j.neuron.2010.11.036
PMCID: PMC3032425  PMID: 21145000
6.  Brain progranulin expression in GRN-associated frontotemporal lobar degeneration 
Acta neuropathologica  2009;119(1):111-122.
Frontotemporal lobar degeneration with TDP- 43 inclusions (FTLD-TDP) is characterized by progressive decline in behavior, executive function, and language. Progranulin (GRN) gene mutations are pathogenic for FTLD-TDP, and GRN transcript haploinsufficiency is the proposed disease mechanism. However, the evidence for this hypothesis comes mainly from blood-derived cells; we measured progranulin expression in brain. We characterized mRNA and protein levels of progranulin from four brain regions (frontal cortex, temporal cortex, occipital cortex, and cerebellum) in FTLD-TDP patients with and without GRN mutations, as well as neurologically normal individuals. Moreover, we performed immunohistochemistry to evaluate the degree of TDP-43 pathology and microglial infiltration present in these groups. In most brain regions, patients with GRN mutations showed mRNA levels comparable to normal controls and to FTLD-TDP without GRN mutations. However, GRN transcript levels in a brain region severely affected by disease (frontal cortex) were increased in mutation-bearing patients. When compared with normal individuals, GRN mutation-bearing cases had a significant reduction in the amount of progranulin protein in the cerebellum and occipital cortex, but not in the frontal and temporal cortices. In GRN mutant cases, GRN mRNA originated from the normal allele, and moderate microglial infiltration was observed. In conclusion, GRN mutation carriers have increased levels of mRNA transcript from the normal allele in brain, and proliferation of microglia likely increases progranulin levels in affected regions of the FTLD-TDP brain, and whether or not these findings underlie the accumulation of TDP-43 pathology in FTLD-TDP linked to GRN mutations remains to be determined.
doi:10.1007/s00401-009-0576-2
PMCID: PMC3104467  PMID: 19649643
Progranulin; TDP-43; Frontotemporal dementia; Frontotemporal lobar degeneration; Microglia
7.  Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions 
Van Deerlin, Vivianna M. | Sleiman, Patrick M. A. | Martinez-Lage, Maria | Chen-Plotkin, Alice | Wang, Li-San | Graff-Radford, Neill R | Dickson, Dennis W. | Rademakers, Rosa | Boeve, Bradley F. | Grossman, Murray | Arnold, Steven E. | Mann, David M.A. | Pickering-Brown, Stuart M. | Seelaar, Harro | Heutink, Peter | van Swieten, John C. | Murrell, Jill R. | Ghetti, Bernardino | Spina, Salvatore | Grafman, Jordan | Hodges, John | Spillantini, Maria Grazia | Gilman, Sid' | Lieberman, Andrew P. | Kaye, Jeffrey A. | Woltjer, Randall L. | Bigio, Eileen H | Mesulam, Marsel | al-Sarraj, Safa | Troakes, Claire | Rosenberg, Roger N. | White, Charles L. | Ferrer, Isidro | Lladó, Albert | Neumann, Manuela | Kretzschmar, Hans A. | Hulette, Christine Marie | Welsh-Bohmer, Kathleen A. | Miller, Bruce L | Alzualde, Ainhoa | de Munain, Adolfo Lopez | McKee, Ann C. | Gearing, Marla | Levey, Allan I. | Lah, James J. | Hardy, John | Rohrer, Jonathan D. | Lashley, Tammaryn | Mackenzie, Ian R.A. | Feldman, Howard H. | Hamilton, Ronald L. | Dekosky, Steven T. | van der Zee, Julie | Kumar-Singh, Samir | Van Broeckhoven, Christine | Mayeux, Richard | Vonsattel, Jean Paul G. | Troncoso, Juan C. | Kril, Jillian J | Kwok, John B.J. | Halliday, Glenda M. | Bird, Thomas D. | Ince, Paul G. | Shaw, Pamela J. | Cairns, Nigel J. | Morris, John C. | McLean, Catriona Ann | DeCarli, Charles | Ellis, William G. | Freeman, Stefanie H. | Frosch, Matthew P. | Growdon, John H. | Perl, Daniel P. | Sano, Mary | Bennett, David A. | Schneider, Julie A. | Beach, Thomas G. | Reiman, Eric M. | Woodruff, Bryan K. | Cummings, Jeffrey | Vinters, Harry V. | Miller, Carol A. | Chui, Helena C. | Alafuzoff, Irina | Hartikainen, Päivi | Seilhean, Danielle | Galasko, Douglas | Masliah, Eliezer | Cotman, Carl W. | Tuñón, M. Teresa | Martínez, M. Cristina Caballero | Munoz, David G. | Carroll, Steven L. | Marson, Daniel | Riederer, Peter F. | Bogdanovic, Nenad | Schellenberg, Gerard D. | Hakonarson, Hakon | Trojanowski, John Q. | Lee, Virginia M.-Y.
Nature genetics  2010;42(3):234-239.
Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA binding protein (TDP-43) inclusions (FTLD-TDP)1. FTLD-TDP is frequently familial resulting from progranulin (GRN) mutations. We assembled an international collaboration to identify susceptibility loci for FTLD-TDP, using genome-wide association (GWA). We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium (LD) block on 7p21 that contains TMEM106B in a GWA study (GWAS) on 515 FTLD-TDP cases. Three SNPs retained genome-wide significance following Bonferroni correction; top SNP rs1990622 (P=1.08×10−11; odds ratio (OR) minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P=2×10−4). TMEM106B variants may confer risk by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in patients with GRN mutations. Our data implicate TMEM106B as a strong risk factor for FTLD-TDP suggesting an underlying pathogenic mechanism.
doi:10.1038/ng.536
PMCID: PMC2828525  PMID: 20154673
8.  Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases 
Journal of neurology  2009;256(8):1205-1214.
Ever since the significance of pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) for human disease has been recognized in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), a number of publications have emerged reporting on this pathology in a variety of neurodegenerative diseases. Given the heterogeneous and, in part, conflicting nature of the recent findings, we here review pathological TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. To this end, we propose a classification scheme in which pathological TDP-43 is the major disease defining pathology in one group, or is present in addition to other neurodegenerative hallmark pathologies in a second category. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders akin to α-synucleinopathies and tauopathies, with the concept of ALS and FTLD-U to be widened to a broad clinico-pathological multisystem disease, i.e., TDP-43 proteinopathy.
doi:10.1007/s00415-009-5069-7
PMCID: PMC2790321  PMID: 19271105
Amyotrophic lateral sclerosis (ALS); Frontotemporal dementia; TDP-43 proteinopathy
9.  Clinical and Pathological Continuum of Multisystem TDP-43 Proteinopathies 
Archives of neurology  2009;66(2):180-189.
Objective
To determine the extent of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system of patients with clinically and autopsy-confirmed diagnoses of frontotemporal lobar degeneration with and without motor neuron disease and amyotrophic lateral sclerosis with and without cognitive impairment.
Design
Performance of immunohistochemical whole–central nervous system scans for evidence of pathological TDP-43 and retrospective clinical medical record review.
Setting
An academic medical center.
Participants
We included 64 patients with clinically and pathologically confirmed frontotemporal lobar degeneration with ubiquitinated inclusions with or without motor neuron disease and amyotrophic lateral sclerosis with or without cognitive impairment.
Main Outcome Measure
Neuronal and glial TDP-43 pathology.
Results
We found evidence of neuronal and glial TDP-43 pathology in all disease groups throughout the neuraxis, albeit with variations in the frequency, morphology, and distribution of TDP-43 lesions. Moreover, the major clinical manifestations (eg, cognitive impairments, motor neuron signs, extrapyramidal symptoms, neuropsychiatric features) were reflected by the predominant distribution and burden of TDP-43 pathology.
Conclusion
These findings strongly suggest that amyotrophic lateral sclerosis, frontotemporal lobar degeneration with amyotrophic lateral sclerosis or motor neuron disease, and frontotemporal lobar degeneration with ubiquitinated inclusions are different manifestations of a multiple-system TDP-43 proteinopathy linked to similar mechanisms of neurodegeneration.
doi:10.1001/archneurol.2008.558
PMCID: PMC2774117  PMID: 19204154
10.  Amyotrophic Lateral Sclerosis–Plus Syndrome With TAR DNA-Binding Protein-43 Pathology 
Archives of neurology  2009;66(1):121-124.
Background
Amyotrophic lateral sclerosis (ALS)–Plus syndromes meet clinical criteria for ALS but also include 1 or more additional features such as dementia, geographic clustering, extrapyramidal signs, objective sensory loss, autonomic dysfunction, cerebellar degeneration, or ocular motility disturbance.
Methods
We performed a whole-brain and spinal cord pathologic analysis in a patient with an ALS-Plus syndrome that included repetitive behaviors along with extrapyramidal and supranuclear ocular motility disturbances resembling the clinical phenotype of progressive supranuclear palsy.
Results
There was motoneuron cell loss and degeneration of the corticospinal tracts. Bunina bodies were present. TAR DNA-binding protein-43 pathology was diffuse. Significant tau pathology was absent.
Conclusions
TAR DNA-binding protein-43 disorders can produce a clinical spectrum of neurodegeneration that includes ALS, frontotemporal lobar degeneration, and ALS with frontotemporal lobar degeneration. The present case illustrates that isolated TAR DNA-binding protein-43 disorders can produce an ALS-Plus syndrome with extrapyramidal features and supranuclear gaze palsy resembling progressive supranuclear palsy.
doi:10.1001/archneur.66.1.121
PMCID: PMC2702763  PMID: 19139310

Results 1-10 (10)