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1.  Vps10 Family Proteins and the Retromer Complex in Aging-Related Neurodegeneration and Diabetes 
Members of the vacuolar protein sorting 10 (Vps10) family of receptors (including sortilin, SorL1, SorCS1, SorCS2, and SorCS3) play pleiotropic functions in protein trafficking and intracellular and intercellular signaling in neuronal and non-neuronal cells. Interactions have been documented between Vps10 family members and the retromer coat complex, a key component of the intracellular trafficking apparatus that sorts cargo from the early endosome to the trans-Golgi network. In recent years, genes encoding several members of the Vps10 family of proteins, as well as components of the retromer coat complex, have been implicated as genetic risk factors for sporadic and autosomal dominant forms of neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease, with risk for type 2 diabetes mellitus and atherosclerosis. In addition to their functions in protein trafficking, the Vps10 family proteins modulate neurotrophic signaling pathways. Sortilin can impact the intracellular response to brain-derived neurotrophic factor (BDNF) by regulating anterograde trafficking of Trk receptors to the synapse and direct control of BDNF levels, while both sortilin and SorCS2 function as cell surface receptors to mediate acute responses to proneurotrophins. This mini-review and symposium will highlight the emerging data from this rapidly growing area of research implicating the Vps10 family of receptors and the retromer in physiological intracellular trafficking signaling by neurotrophins and in the pathogenesis of neurodegeneration.
doi:10.1523/JNEUROSCI.3359-12.2012
PMCID: PMC3576841  PMID: 23055476
2.  Overcoming obstacles to repurposing for neurodegenerative disease 
Repurposing Food and Drug Administration (FDA)-approved drugs for a new indication may offer an accelerated pathway for new treatments to patients but is also fraught with significant commercial, regulatory, and reimbursement challenges. The Alzheimer’s Drug Discovery Foundation (ADDF) and the Michael J. Fox Foundation for Parkinson’s Research (MJFF) convened an advisory panel in October 2013 to understand stakeholder perspectives related to repurposing FDA-approved drugs for neurodegenerative diseases. Here, we present opportunities on how philanthropy, industry, and government can begin to address these challenges, promote policy changes, and develop targeted funding strategies to accelerate the potential of FDA-approved repurposed drugs.
doi:10.1002/acn3.76
PMCID: PMC4184781  PMID: 25356422
3.  Protein Sorting Motifs in the Cytoplasmic Tail of SorCS1 Control Generation of Alzheimer’s Amyloid-β Peptide 
Endosomal sorting of the Alzheimer amyloid precursor protein (APP) plays a key role in the biogenesis of the amyloid-β peptide (Aβ). Genetic lesions underlying Alzheimer disease (AD) can act by interfering with this physiological process. Specifically, proteins involved in trafficking between endosomal compartments and the trans Golgi network (TGN) (including the retromer complex (Vps35, Vps26) and its putative receptors (sortilin, SorL1, SorCS1) have been implicated in the molecular pathology of late onset-AD. Previously, we demonstrated a role for SorCS1 in APP metabolism and Aβ production and, while we implicated a role for the retromer in this regulation, the underlying mechanism remained poorly understood. Here, we provide evidence for a motif within the SorCS1c cytoplasmic tail that, when manipulated, results in perturbed sorting of APP and/or its fragments to endosomal compartments, decreased retrograde TGN trafficking, and increased Aβ production in H4 neuroglioma cells. These perturbations apparently do not involve turnover of the cell-surface APP pool, but rather they involve intracellular APP and/or its fragments, downstream of APP endocytosis.
doi:10.1523/JNEUROSCI.5270-12.2013
PMCID: PMC3696125  PMID: 23595767
4.  Progress in novel cognitive enhancers for cognitive aging and Alzheimer’s disease 
Increased knowledge of the biology of synaptic function has led to the development of novel cognitive-enhancing therapeutic strategies with the potential for increased efficacy and safety. This editorial highlights a diverse array of approaches currently being explored to target cognitive dysfunction due to aging and/or Alzheimer’s disease.
doi:10.1186/alzrt209
PMCID: PMC3979029  PMID: 24083622
5.  Diverse therapeutic targets and biomarkers for Alzheimer's disease and related dementias: report on the Alzheimer's Drug Discovery Foundation 2012 International Conference on Alzheimer's Drug Discovery 
The Alzheimer's Drug Discovery Foundation's 13th International Conference on Alzheimer's Drug Discovery was held on 10-11 September 2012 in Jersey City, NJ, USA. This meeting report provides an overview of Alzheimer's Drug Discovery Foundation-funded programs, ranging from novel biomarkers to accelerate clinical development to drug-discovery programs with a focus on targets related to neuroprotection, mitochondrial function, apolipoprotein E and vascular biology.
doi:10.1186/alzrt159
PMCID: PMC3580332  PMID: 23374760
6.  Beyond amyloid: a diverse portfolio of novel drug discovery programs for Alzheimer's disease and related dementias 
Although the molecular mechanisms underlying the pathogenesis of Alzheimer's disease and other related neurodegenerative diseases remain unclear, accumulation of misfolded proteins, neuroinflammation, mitochondrial dysfunction and perturbed calcium homeostasis have been identified as key events leading to neuronal loss during neurodegeneration. Evidence for 'druggable' targets for each of these key mechanisms was presented by the Alzheimer's Drug Discovery Foundation-funded investigators at the 12th International Conference on Alzheimer's Drug Discovery, Jersey City, NJ, 26-27 September 2011 http://www.worldeventsforum.com/addf/addrugdiscovery.
doi:10.1186/alzrt99
PMCID: PMC3308025  PMID: 22236739
7.  Diabetes-associated SorCS1 regulates Alzheimer’s amyloid-β metabolism: Evidence for involvement of SorL1 and the retromer complex 
The Journal of Neuroscience  2010;30(39):13110-13115.
SorCS1 and SorL1/SorLA/LR11 belong to the sortilin family of vacuolar protein sorting-10 (Vps10) domain-containing proteins. Both are genetically associated with Alzheimer’s disease (AD), and SORL1 expression is decreased in the brains of patients suffering from AD. SORCS1 is also genetically associated with types 1 and 2 diabetes mellitus (T1DM, T2DM). We have undertaken a study of the possible role(s) for SorCS1 in metabolism of the Alzheimer’s amyloid-β peptide (Aβ) and the Aβ precursor protein (APP), to test the hypothesis that Sorcs1-deficiency might be a common genetic risk factor underlying the predisposition to AD that is associated with T2DM. Overexpression of SorCS1Cβ-myc in cultured cells caused a reduction (p=0.002) in Aβ generation. Conversely, endogenous murine Aβ40 and Aβ42 levels were increased (Aβ40, p=0.044; Aβ42, p=0.007) in the brains of female Sorcs1 hypomorphic mice, possibly paralleling the sexual dimorphism that is characteristic of the genetic associations of SORCS1 with AD and DM. Since SorL1 directly interacts with Vps35 to modulate APP metabolism, we investigated the possibility that SorCS1Cβ-myc interacts with APP, SorL1, and/or Vps35. We readily recovered SorCS1:APP, SorCS1:SorL1, and SorCS1:Vps35 complexes from nontransgenic mouse brain. Notably, total Vps35 protein levels were decreased by 49% (p=0.009) and total SorL1 protein levels were decreased by 29% (p=0.003) in the brains of female Sorcs1-hypomorphic mice. From these data, we propose that dysfunction of SorCS1 may contribute to both the APP/Aβ disturbance underlying AD and the insulin/glucose disturbance underlying DM.
doi:10.1523/JNEUROSCI.3872-10.2010
PMCID: PMC3274732  PMID: 20881129
AD; T1DM; T2DM; protein trafficking; APP; SorCS1; Vps10 domain; retromer
8.  Protein kinase C and rho activated coiled coil protein kinase 2 (ROCK2) modulate Alzheimer's APP metabolism and phosphorylation of the Vps10-domain protein, SorL1 
Background
Generation of the amyloid β (Aβ) peptide of Alzheimer's disease (AD) is differentially regulated through the intracellular trafficking of the amyloid β precursor protein (APP) within the secretory and endocytic pathways. Protein kinase C (PKC) and rho-activated coiled-coil kinases (ROCKs) are two "third messenger" signaling molecules that control the relative utilization of these two pathways. Several members of the Vps family of receptors (Vps35, SorL1, SorCS1) play important roles in post-trans-Golgi network (TGN) sorting and generation of APP derivatives, including Aβ at the TGN, endosome and the plasma membrane. We now report that Vps10-domain proteins are candidate substrates for PKC and/or ROCK2 and act as phospho-state-sensitive physiological effectors for post-TGN sorting of APP and its derivatives.
Results
Analysis of the SorL1 cytoplasmic tail revealed multiple consensus sites for phosphorylation by protein kinases. SorL1 was subsequently identified as a phosphoprotein, based on sensitivity of its electrophoretic migration pattern to calf intestine alkaline phosphatase and on its reaction with anti-phospho-serine antibodies. Activation of PKC resulted in increased shedding of the ectodomains of both APP and SorL1, and this was paralleled by an apparent increase in the level of the phosphorylated form of SorL1. ROCK2, the neuronal isoform of another protein kinase, was found to form complexes with SorL1, and both ROCK2 inhibition and ROCK2 knockdown enhanced generation of both soluble APP and Aβ.
Conclusion
These results highlight the potential importance of SorL1 in elucidating phospho-state sensitive mechanisms in the regulation of metabolism of APP and Aβ by PKC and ROCK2.
doi:10.1186/1750-1326-5-62
PMCID: PMC3036620  PMID: 21192821

Results 1-8 (8)