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.