bioRxiv : the preprint server for biology · 2024
Neurodegenerative and neurodevelopmental roles for bulk lipid transporters VPS13A and BLTP2 in movement disorders.
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Neuman Sarah D, Thakur Rajan S, Gratz Scott J, O'Connor-Giles Kate M, Bashirullah Arash
Аннотация
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.
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.