Neurodegenerative and neurodevelopmental roles for bulk lipid transporters and in movement disorders.

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 and in movement disorder pathogenesis using models.

METHODS

We generated tissue-specific knockdowns of the ortholog ( ) and the ortholog ( ) in neurons and muscles of . We analyzed age-dependent locomotor behavior, neurodegeneration, and synapse development and function.

RESULTS

Neuron-specific loss of the 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 disease. In contrast, neuronal loss of the ortholog resulted in severe early-onset locomotor defects without neurodegeneration, while muscle loss impaired synaptogenesis and neurotransmission at the neuromuscular junction (NMJ).

CONCLUSIONS

maintains neuronal survival, while orchestrates synaptic development. 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.