Parkinson's Disease-Associated Protein VPS13C Regulates Phospho-Rab10-Mediated Lysosomal Function in Human iPSC-Derived Dopaminergic Neurons

Neurodegenerative diseases are progressive disorders with age as the greatest risk factor. Parkinson’s disease (PD) is the most common movement disorder and the second most common neurodegenerative disease after Alzheimer’s disease. A stark increase in the incidence of neurodegenerative diseases is predicted due to the aging population worldwide (Dorsey et al., 2007; Poewe et al., 2017). However, no disease-modifying treatments for PD are currently available. The neuroscience field focuses on understanding the underlying disease mechanisms, which will help to identify targets for future therapeutics and the identification of disease-specific biomarkers to diagnose patients before the onset of movement-related symptoms. Lysosomes seem to play an essential role in several monogenic and sporadic forms of PD and synucleinopathies (Burbulla et al., 2017; Mazzulli et al., 2011; Nalls et al., 2019). Genetic models of Parkinson’s disease are utilized to initially identify and understand underlying disease mechanisms and to later validate the gained knowledge in more common forms of PD with the hope to better understand this complex disease and improve Parkinson’s disease patient care. Rare loss-of function mutations in Vacuolar Protein Sorting 13 Homolog C (VPS13C) have recently been associated with an aggressive form of early-onset Parkinson’s disease (Lesage et al., 2016). The function of VPS13C protein however remains poorly understood. Previous studies have been conducted in non-neuronal cells and suggest a potential role for VPS13C in mitochondrial integrity (Lesage et al., 2016) and at lipid transfer at ER-lysosome contact sites (Kumar et al., 2018). However, the function of VPS13C in Parkinson’s disease-relevant human dopaminergic neurons has not yet been investigated. This thesis established a PD-relevant model using human induced pluripotent stem cell-derived dopaminergic neurons and identified an important role for VPS13C in lysosomal homeostasis. VPS13C-deficient neurons exhibited significantly enlarged lysosomes with increased inter-lysosomal contact sites and decreased organelle motility. Additionally, these neurons showed a decreased lysosomal hydrolytic capacity and acidification, suggesting an underlying lysosomal dysfunction upon loss of VPS13C. Several biochemical approaches identified small GTPase Rab10 as a phospho-dependent novel interactor of VPS13C on lysosomes. Mechanistic studies further elucidated a function for VPS13C together with phosphorylated Rab10 in a lysosomal stress response pathway. Thus, this work establishes a role of VPS13C in regulating lysosomal dynamics and function in human dopaminergic neurons and implicated lysosomal dysfunction as a key driver of VPS13C-associated Parkinson’s disease.

Level thesis:degree_level

thesis.doctoral

Grantor dc:publisher

Universität Bielefeld

Year

2025

Author dc:creator

• Schröder, Leonie Franziska

Repository record source_url

https://pub.uni-bielefeld.de/record/3000125

OAI identifier oai:identifier

oai:pub.uni-bielefeld.de:3000125