Regulation of sortilin-1 by neuron-specific genes; implications for ad and FTD - sortilin-1 (SORT1) belongs to the VPS10P-domain containing receptors that also includes sorla and SORCS1-3. Previous…

Regulation of sortilin-1 by neuron-specific genes; implications for ad and FTD - sortilin-1 (SORT1) belongs to the VPS10P-domain containing receptors that also includes sorla and SORCS1-3. Previous studies have implicated SORT1 as a key regulator of pathological processes in alzheimer's disease (ad) and frontotemporal dementia (FTD). For instance, a recent genome-wide association study (GWAS) identified SORT1 as a novel risk allele for late-onset ad, and gave SORT1 a tier 1 priority score for future investigations based on quantitative trait loci analysis. SORT1 is also a receptor that helps regulate the availability of progranulin (PGRN), one of the three most common genetic causes of familial frontotemporal lobar degeneration (FTLD). Molecular studies have shown that SORT1 is proteolytically processed into a large extracellular amino-terminus (ECTODOMAIN) and a small carboxy-terminal fragment (CTF). Interestingly, these sortilin C-terminal fragments (SORFRA) accumulate as novel senile plaque-like lesions in human ad patient brain samples, but not in rodent or primate models of ad, suggesting a possible human-specific aspect of ad/FTD pathology. However, while a significant body of work has linked SORT1 with ad and FTD, much less is known regarding the molecular mechanisms of SORT1 processing itself. We performed preliminary protein interactome screens of SORT1 and identified NSG1 and NSG2 as binding partners of SORT1, proteins that have never previously been associated with ad or FTD. Our preliminary data confirm the NSG-SORT1 interactions, and further demonstrate that NSG1 is downregulated in post-mortem brain samples from both ad and FTD patients. In addition, this is correlated with differential SORT1 processing, where reduced NSG1 correlates with increased CTF levels. The studies proposed in this application are designed to test the exciting and novel hypothesis that NSG1 and NSG2 are altered in the brains of ad/FTD patients, and whether these alterations may differentially affect SORT1 proteolytic cleavage and/or trafficking. We propose to explore this hypothesis through two specific aims, the first of which will make use of post-mortem human and rodent brain samples to correlate NSG1-2 expression levels with ad/FTD disease subtypes and SORT1 proteolytic processing. The second aim will then use in vitro human and rodent neurons to test whether altering levels of NSG1-2 differentially affects SORT1 processing, trafficking, as well as ad/FTD-related pathology (phosphorylated TAU and TDP-43, as well as AΒ levels). The results of the proposed studies will identify novel molecular mechanisms that may underlie the progression of ad/FTD pathology, and provide critical preliminary data and scientific rationale to initiate a new avenue of study and the possible development of novel therapeutics for ad and FTD.