# Regulation of Sortilin-1 by Neuron-Specific Genes; implications for AD and FTD

> **NIH NIH R21** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2024 · $419,375

## Abstract

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.

## Key facts

- **NIH application ID:** 10871244
- **Project number:** 1R21AG086934-01
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** JASON P WEICK
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $419,375
- **Award type:** 1
- **Project period:** 2024-06-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871244

## Citation

> US National Institutes of Health, RePORTER application 10871244, Regulation of Sortilin-1 by Neuron-Specific Genes; implications for AD and FTD (1R21AG086934-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10871244. Licensed CC0.

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