# Interplay between macroautophagy and secretory autophagy in neurons.

> **NIH NIH F32** · UNIVERSITY OF PENNSYLVANIA · 2024 · $77,284

## Abstract

Neurons rely on autophagy to constitutively degrade damaged proteins and organelles to maintain neuronal
homeostasis. When neuronal autophagy capacity is overwhelmed, aggregated proteins and damaged organelles
accumulate and contribute to neuronal dysfunction or death. Indeed, autophagy dysfunction is consistently
associated with neurodegenerative diseases, such as Parkinson’s Disease. How do neurons respond when
faced with the accumulation of dysfunctional proteins and organelles that overwhelm autophagy? Do neurons
employ alternate quality control mechanisms? Recent findings suggest that autophagy-dependent degradation
and autophagy-dependent secretion can act in coordination to regulate cellular homeostasis in non-neuronal cell
types. When autophagosome maturation is impeded, autophagy-dependent secretion of extracellular vesicles
(EVs) can be initiated as a mechanism to unburden the degrative machinery. Whether neurons similarly
extrude damaged material via autophagy dependent secretion is unclear. I hypothesize that stressed
neurons engage autophagy-dependent secretion as an alternate quality control mechanism to dispel
cellular waste, e.g., mitochondria, which is then internalized by surrounding astrocytes. This model is
supported by my preliminary findings that neurons with reduced capacity for autophagy upregulate secretion of
EVs. Of particular interest, I find that mitochondrial proteins are shunted from degradation toward a secretory
fate in chronically stressed neurons. These observations have important implications in neurodegenerative
diseases where autophagy is strained, and the expulsion of mitochondria could heighten systemic inflammatory
responses. This proposal will contribute to our fundamental understanding of neuronal homeostasis mechanisms
and could reveal important clues underlying neurodegenerative disease.
In Aim 1, I test the hypothesis that stressed neurons shunt autophagy cargo toward secretion via secretory
autophagy. I will track secretion of EVs from neurons facing chronic or acute autophagic stress and determine
which autophagy proteins are required for compensatory secretion. Using immunoblotting and high-resolution
microscopy, I will confirm the secretory autophagy pathway prompting secretion in stressed neurons. Finally, I
will use proteomics to molecularly profile the cargo expelled via autophagy dependent secretion.
In Aim 2, I test the hypothesis that neurons expel mitochondria for transcellular internalization. I will use neuronal-
astrocyte co-culture to visualize neuronal mitochondria internalized by nearby astrocytes. Next, I will track
astrocyte engulfment of neuronal mitochondria in vivo.

## Key facts

- **NIH application ID:** 11037881
- **Project number:** 5F32NS129586-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Sierra Danielle Palumbos
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $77,284
- **Award type:** 5
- **Project period:** 2023-09-11 → 2026-02-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11037881

## Citation

> US National Institutes of Health, RePORTER application 11037881, Interplay between macroautophagy and secretory autophagy in neurons. (5F32NS129586-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/11037881. Licensed CC0.

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