# Neuronal roles of Parkinsons Disease Vps13C in regulating autophagy and calcium dynamics

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $499,301

## Abstract

With a rapidly aging population, neurodegenerative diseases such as Parkinson’s Disease (PD), are expected
to rise to 25% by 2030, presenting a huge economical and emotional challenge to society. While most PD cases
are sporadic, approximately 10-15% are familial. One of the few genes leading to early-onset PD is the recently
discovered VPS13C (Vacuolar Protein Sorting 13 Homolog C). Autosomal-recessive mutations in Vps13C result
in protein-truncation and loss of function, with patients demonstrating Lewy body pathology with α-synuclein
aggregation in both dopaminergic and cortical neurons. While Vps13C was recently implicated in the
endolysosomal pathway in non-neuronal cells, its neuronal function and how loss of this function leads to PD in
patient neurons still remains to be elucidated. Through an unbiased mass-spectrometry based screen, we
recently identified Vps13C as a novel interactor of Ykt6, a soluble N-ethylmaleimide sensitive factor attachment
protein receptor (SNARE) protein critically involved in the endolysosomal pathway and linked to the pathobiology
of α-synuclein. Interestingly, we further found that the Ykt6 and Vps13C interaction was regulated by the
phosphatase activity of Calcineurin, a master regulator of Ca2+ signaling and a key player of toxicity in several
PD models. Importantly, we demonstrated that the Calcineurin-dependent phosphorylation site in Ykt6 is a critical
regulatory step mediating autophagosome to lysosome fusion during autophagy, and Vps13C can further
regulate autophagy. Based on strong preliminary data, the goals of this proposal are to investigate the role for
Vps13C in regulating neuronal autophagy via its interaction with Ykt6 (Aim 1) and its functional dependence on
Ca2+ dynamics mediated by Calcineurin activity (Aim 2) in PD. Our central hypothesis is that loss of Vps13C
misregulates neuronal autophagy and Ca2+ dynamics, contributing to PD pathogenesis in patient neurons. The
proposed studies will test our hypotheses using induced pluripotent stem cell (iPSC)-derived human midbrain
dopamine (DA) neurons from patients carrying VPS13C truncation mutations, as well as iPSC-human DA neuron
CRISPR/Cas9-generated VPS13C knockout lines. To address this, we will implement: 1) micropatterned
substrates which we have generated which allow for the culture of individually separated neurons over extended
periods of time, 2) affinity purification coupled to mass spectrometry (AP-MS) analysis of Vps13C’s interactome
under both basal and stressed conditions, 3) neuronal imaging of Vps13C dynamics and function using state-of-
the-art imaging techniques available at Northwestern University’s Nikon Imaging Center Microscopy Core
including live cell super-resolution microscopy, and 4) advanced organelle-specific Ca2+ and lipid sensor imaging
techniques in PD patient-derived DA neurons to further elucidate Vps13C function. These studies will provide a
mechanistic understanding of Vps13C’s role in autophagy and Ca2+ signa...

## Key facts

- **NIH application ID:** 10029243
- **Project number:** 1R01NS117750-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Gabriela CaraveoPiso
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $499,301
- **Award type:** 1
- **Project period:** 2020-09-30 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10029243

## Citation

> US National Institutes of Health, RePORTER application 10029243, Neuronal roles of Parkinsons Disease Vps13C in regulating autophagy and calcium dynamics (1R01NS117750-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10029243. Licensed CC0.

---

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