VPS13C-mediated endoplasmic reticulum-lysosome tethering in neuronal stress responses

Area of Science:

• Cell Biology
• Neuroscience
• Molecular Biology

Background:

• Organelle contact sites are crucial for cellular communication, coordinating lipid transfer, ion signaling, and metabolism.
• In neurons, endoplasmic reticulum (ER), lysosome, and mitochondria communication is vital for homeostasis.
• Vacuolar protein sorting 13 homolog C (VPS13C) is identified as a key lipid transporter mediating ER-lysosome tethering and lysosomal stress response.

Purpose of the Study:

• To review the role of VPS13C in ER-lysosome tethering and its implications in cellular damage response.
• To explore how VPS13C-mediated contacts contribute to membrane repair, metabolic coordination, and transcriptional adaptation.
• To discuss the link between VPS13C dysfunction, disrupted organelle networks, and Parkinson's disease pathogenesis.

Main Methods:

• Structural analysis of VPS13 family proteins to understand their lipid transport channel function.
• Investigating VPS13C recruitment to ER-lysosome contact sites following lysosomal damage.
• Examining the proximity of ER-lysosome contacts to ER-mitochondria junctions to understand multi-organelle signaling hubs.

Main Results:

• VPS13C forms tethering bridges at ER-lysosome contact sites, facilitating high-capacity lipid transfer for membrane repair.
• ER-lysosome contacts, often near ER-mitochondria junctions, form signaling hubs influencing calcium, lipid redistribution, and mitochondrial adaptation.
• Disruption of VPS13C function is linked to Parkinson's disease, affecting lysosomal homeostasis and interacting with pathogenic pathways like alpha-synuclein aggregation.

Conclusions:

• ER-lysosome tethering by VPS13C is integral to a staged cellular damage response, encompassing membrane repair, metabolic regulation, and transcriptional changes.
• VPS13C-mediated organelle communication networks are essential for neuronal health, and their disruption contributes to neurodegenerative diseases.
• Understanding VPS13C's role provides a framework for exploring therapeutic strategies targeting organelle dysfunction in Parkinson's disease.