Neurodegenerative and neurodevelopmental roles for bulk lipid transporters VPS13A and BLTP2 in movement disorders

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. Objectives To determine the age-of-onset and tissue-specific roles of VPS13A and BLTP2 in movement disorder pathogenesis 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 age- onset movement deficits and reduced lifespan, while muscle-specific loss affected only lifespan, revealing neurodegeneration and myopathy as independent comorbidities in VPS13A disease. In contrast, neuronal loss of the BLTP2 ortholog resulted in severe early-onset locomotor defects without neurodegeneration, while muscle loss impaired synaptogenesis and neurotransmission at the neuromuscular junction (NMJ). Conclusions VPS13A maintains neuronal survival, while BLTP2 orchestrates synaptic development. VPS13A function in muscle does not play a role in movement defects. The phenotypic specificity of BLTP function provides mechanistic insights into distinct disease trajectories for BLTP-associated movement disorders.