# Regulation of Mitochondrial Dynamics by ERAD

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $325,001

## Abstract

Novel Role of SEL1L-HRD1 ERAD in Pathogenesis of Alzheimer’s Disease
ABSTRACT
Neurons face a complex challenge of balancing protein folding and degradation in the endoplasmic
reticulum (ER). Indeed, altered ER proteostasis has been implicated in the pathogenesis of
neurodegeneration including Alzheimer’s disease; however, the underlying molecular mechanisms remain
largely unknown. To date, the role of ER-associated degradation (ERAD), the first line of defense by
clearing misfolded ER proteins for cytosolic proteasomal degradation, in neurons remains unknown. Sel1L-
Hrd1 protein complex represents the most conserved ERAD branch with Sel1L being the cofactor for the E3
ligase Hrd1. We recently generated pan-neuron-specific Sel1L-deficient (Sel1LSynCre) mice and found that,
even before weaning, Sel1LSynCre mice exhibit signs of neurodegeneration, pointing to a cell-autonomous
role of Sel1L in neuronal function in neurodegeneration. Providing further support to clinical relevance and
importance of Sel1L, Sel1L SNP has identified in Finnish canines suffering early-onset cerebellar ataxia. In
this administrative supplement, we propose to test an overarching hypothesis that Sel1L-Hrd1 ERAD plays
a crucial role in neurodegeneration including Alzheimer’s disease by preventing the accumulation and
aggregation of misfolded proteins in the ER, thereby ensuring biogenesis of nascent receptor(s) and
neurotransmitter(s). Taking advantage of the advances obtained in this parent grant, we propose to address
two of the following Aims: (1) determine whether and how SEL1L-HRD1 ERAD expression is altered in AD
neurons; and (2) Identify the SEL1L-interacting network and ERAD substrates in healthy and AD neurons.
Indeed, this study is made possible by our recent effort that has led to the generation and validation of
several human SEL1L-specific antibodies for both immunoprecipitation and immunostaining. In completing
this project, we will not only provide novel insights into the molecular events underlying SEL1L-HRD1 ERAD
function in maintaining neuronal health, but also identify potential targets for manipulating the turnover of
nascent ER proteins as an approach for the treatment of neurodegeneration.

## Key facts

- **NIH application ID:** 10113701
- **Project number:** 3R35GM130292-02S1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ling Qi
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $325,001
- **Award type:** 3
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113701

## Citation

> US National Institutes of Health, RePORTER application 10113701, Regulation of Mitochondrial Dynamics by ERAD (3R35GM130292-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10113701. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*