# Dynamics of Axonal Autophagy in Neurons

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $423,594

## Abstract

Project Summary
Autophagy is an essential cellular degradative pathway triggered by environmental stress in many cell types. In
neurons, autophagy has a further role as a constitutively active mechanism that maintains axonal homeostasis.
In vitro and in vivo, autophagosomes are generated de novo at axon terminals and synaptic sites. Once formed,
axonal autophagosomes are trafficked back to the soma by the retrograde microtubule motor protein cytoplasmic
dynein. Autophagosomes mature en route through fusion with late endosomes and lysosomes. Cargo
degradation also occurs during transport along the axon, leading to the somal delivery of digested contents for
recycling in new biosynthetic pathways. Axonal autophagy degrades mitochondrial fragments and disease-
associated protein aggregates, suggesting a key role in the maintenance of axonal homeostasis. Consistent with
this hypothesis, neuron-specific ablation of autophagy is sufficient to cause neurodegeneration. However, many
outstanding questions remain that must be addressed: How is autophagy regulated in neurons? What controls
the localization and timing of autophagosome formation and cargo engulfment? What is the function of axonal
autophagy – what cargos are targeted for degradation, and by what mechanisms? And how does the axonal
autophagy pathway intersect with the endolysosomal pathway to effectively degrade cargos such as
dysfunctional organelles and aggregated proteins? To address these questions, we will use live cell imaging in
primary neurons and gene-edited iPSC-derived human neurons, in concert with biochemical and biophysical
approaches including proteomic analysis and computational modeling, to query the basic mechanisms of axonal
autophagy and how these mechanisms are perturbed by neuronal stressors including mitochondrial dysfunction,
protein aggregation, and lysosomal damage. We will address the following specific aims: Aim 1: How is
autophagy spatially and temporally regulated in neurons? What controls the initiation of autophagy at the axon
terminal or presynaptic sites? Aim 2: What cargos are degraded by axonal autophagy? Is cargo engulfment a
selective process, or nonspecific? Is there preferential uptake of some cargos, and if so, what are these cargos?
What mechanisms control cargo uptake? And Aim 3: How does the autophagy pathway intersect with the
lysosomal pathway? How is autophagosome-lysosome fusion regulated? Why is axonal autophagy so
dependent on retrograde axonal transport? And what mechanisms regulate lysosomal health along the axon,
as lysosomes are required for the effective clearance of engulfed cargos by autophagy. Given the essential and
conserved role that autophagy plays in neurons, we anticipate that these studies will significantly advance our
understanding of neuronal cell biology, providing important insights into the mechanisms maintaining axonal.
homeostasis and how the perturbation of these mechanisms may lead to neurodegeneration. We hope that the...

## Key facts

- **NIH application ID:** 10396599
- **Project number:** 5R01NS060698-14
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Erika L Holzbaur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,594
- **Award type:** 5
- **Project period:** 2008-07-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10396599

## Citation

> US National Institutes of Health, RePORTER application 10396599, Dynamics of Axonal Autophagy in Neurons (5R01NS060698-14). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10396599. Licensed CC0.

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