# The connection between ER-phagy, ER structure and hereditary spastic paraplegias

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $478,601

## Abstract

Project Summary
The degradation of misfolded proteins in the endoplasmic reticulum (ER) by the ER-associated degradation
(ERAD) pathway prevents potentially toxic proteins from entering the secretory pathway. ERAD, however,
cannot clear all proteins from the ER. For example, some proteins, such as aggregation-prone proteins,
large polymers and fibrillar proteins, are resistant to degradation by ERAD and must be disposed of by
alternate disposal pathways. As aggregation prone proteins have been to linked to neurodegenerative
diseases, understanding how these alternate disposal pathways function is of medical importance.
 ER autophagy (ER-phagy) is a disposal pathway that degrades ER domains and aggregation-prone
proteins. How specific domains, on the continuous network of the ER, are targeted for degradation is
unknown. We have found that a non-canonical form of the COPII coat, that contains SEC24C-SEC23,
works with receptors on the ER to target domains for autophagy. ER-phagy sites (ERPHS) on the ER are
distinct from the ER exit sites where secretory cargo is loaded into canonical COPII coated vesicles that
traffic to the Golgi. Our findings suggest that ER structure may be important for the formation of ERPHS.
Additionally, mutations in several ER shaping proteins, associated with hereditary spastic paraplegias
(HSP), lead to defects in ER-phagy. These findings suggest a link between ER-phagy, the formation of the
ERPHS and HSP.
 In this proposal I describe several aims that are designed to address the role that ER structure plays
in the formation of ERPHS and the link between ERPHS formation and HSP. Specifically, we will perform
live cell imaging and mass spectroscopy experiments to characterize the ERPHS and their cargo. Misfolded
proteins, known to be degraded by ER-phagy, will be analyzed. To date six ER autophagy receptors have
been identified. Our studies will address when SEC24C interacts with the autophagy machinery and which
of the six known receptors interact with SEC24C. Our biochemical studies may lead to the identification of
new proteins that interact with SEC24C during ER autophagy. Autophagy reporters, imaging analysis and
biochemical studies will be used to address the role that ER organization and ER shaping proteins play in
ER-phagy and ERPHS formation. The proteins we will analyze in Aim 2 and Aim 3 are associated with HSP
and HSP-like neuropathies. In total, these studies will shed light on the link between ER structure, ERPHS
formation and HSP.

## Key facts

- **NIH application ID:** 10617731
- **Project number:** 5R01NS117440-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Susan FERRO-NOVICK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $478,601
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10617731

## Citation

> US National Institutes of Health, RePORTER application 10617731, The connection between ER-phagy, ER structure and hereditary spastic paraplegias (5R01NS117440-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10617731. Licensed CC0.

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