Neurodegenerative and Neurodevelopmental Roles for Bulk Lipid Transporters VPS13A and BLTP2.

Abstract

Background: Bridge-like lipid transfer proteins (BLTPs) mediate bulk lipid transport at membrane contact sites. Mutations in BLTPs are linked to both early-onset neurodevelopmental and later-onset neurodegenerative diseases, including movement disorders. The tissue specificity and temporal requirements of BLTPs in disease pathogenesis remain poorly understood.

Objective: The objective of this study was to determine tissue-specific and aging-dependent roles for VPS13A and BLTP2 using Drosophila models.

Methods: We generated tissue-specific knockdowns of the VPS13A ortholog (Vps13) and the BLTP2 ortholog (hobbit) in neurons and muscles of Drosophila. We analyzed age-dependent locomotor behavior, neurodegeneration, and synapse development and function.

Results: Neuron-specific loss of the VPS13A ortholog caused neurodegeneration followed by aging-dependent movement deficits and reduced lifespan, whereas muscle-specific loss affected only lifespan. In contrast, neuronal loss of the BLTP2 ortholog resulted in severe early-onset locomotor defects without neurodegeneration, whereas muscle loss impaired synaptogenesis and neurotransmission at the neuromuscular junction.

Conclusions: VPS13A maintains neuronal survival, whereas BLTP2 orchestrates synaptic development. The phenotypic specificity of BLTP function provides mechanistic insights into distinct disease trajectories for BLTP-associated disorders. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.