ALS-Linked VapB P56S Mutation Alters Neuronal Mitochondrial Turnover at the Synapse

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Mitochondrial homeostasis is crucial for neuronal function and survival.
• Endoplasmic reticulum (ER)-mitochondrial contact sites regulate mitochondrial dynamics.
• Vesicle-associated membrane protein-associated protein B (VapB) is an ER protein at these contact sites, and a mutation (P56S) is linked to amyotrophic lateral sclerosis (ALS) type 8.

Purpose of the Study:

• To investigate the role of VapB in neuronal mitochondrial population maintenance.
• To determine how the VapB P56S mutation affects mitochondrial homeostasis.
• To elucidate the mechanism by which VapB controls mitochondrial turnover.

Main Methods:

• Transgenic zebrafish larvae expressing wild-type VapB and VapB P56S.
• Genetic manipulation to alter mitochondrial biogenesis.
• Assessment of mitochondrial biogenesis and mitophagy in axon terminals.
• Utilizing a synthetic ER-mitochondrial tether.

Main Results:

• Transgenic VapB P56S expression increased mitochondrial biogenesis and population size in axon terminals.
• Wild-type VapB expression increased mitophagy, balancing biogenesis.
• VapB P56S mutants showed impaired mitophagy, failing to compensate for increased biogenesis.
• VapB's role in mitochondrial turnover appears independent of ER-mitochondrial tethering.

Conclusions:

• VapB regulates mitochondrial turnover in neuronal axon terminals.
• The ALS-linked VapB P56S mutation impairs mitophagy, disrupting mitochondrial population control.
• This impaired VapB function may contribute to neurodegeneration observed in ALS type 8.