PUBLICATION
ALS-linked VapB P56S mutation alters neuronal mitochondrial turnover at the synapse
- Authors
- Wong, H.C., Lang, A.E., Stein, C., Drerup, C.M.
- ID
- ZDB-PUB-240727-28
- Date
- 2024
- Source
- The Journal of neuroscience : the official journal of the Society for Neuroscience 44(35): (Journal)
- Registered Authors
- Drerup, Katie (Catherine)
- Keywords
- none
- MeSH Terms
-
- Mutation
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Mitophagy/genetics
- Mitophagy/physiology
- Mitochondria*/genetics
- Mitochondria*/metabolism
- Animals
- Humans
- Vesicular Transport Proteins/genetics
- Vesicular Transport Proteins/metabolism
- Synapses*/genetics
- Synapses*/metabolism
- Amyotrophic Lateral Sclerosis*/genetics
- Amyotrophic Lateral Sclerosis*/metabolism
- Amyotrophic Lateral Sclerosis*/pathology
- Neurons/metabolism
- Zebrafish*
- Endoplasmic Reticulum/genetics
- Endoplasmic Reticulum/metabolism
- Animals, Genetically Modified*
- PubMed
- 39054069 Full text @ J. Neurosci.
Citation
Wong, H.C., Lang, A.E., Stein, C., Drerup, C.M. (2024) ALS-linked VapB P56S mutation alters neuronal mitochondrial turnover at the synapse. The Journal of neuroscience : the official journal of the Society for Neuroscience. 44(35):.
Abstract
Mitochondrial population maintenance in neurons is essential for neuron function and survival. Contact sites between mitochondria and the endoplasmic reticulum (ER) are poised to regulate mitochondrial homeostasis in neurons. These contact sites can function to facilitate transfer of calcium and lipids between the organelles and have been shown to regulate aspects of mitochondrial fission and fusion dynamics. VapB is an ER membrane protein present at a subset of ER-mitochondria contact sites. Mutations in VapB cause neurodegenerative disease. Specifically, a proline-to-serine mutation at amino acid 56 (P56S), correlates with susceptibility to amyotrophic lateral sclerosis (ALS) type 8. Given the relationship between failed mitochondrial health and neurodegenerative disease, we investigated the function of VapB in mitochondrial population maintenance. We demonstrate that transgenic expression of VapBP56S in zebrafish larvae (sex undetermined) increased mitochondrial biogenesis, causing increased mitochondrial population size in the axon terminal. Expression of wild type VapB did not alter biogenesis but, instead, increased mitophagy in the axon terminal. Using genetic manipulations to independently increase mitochondrial biogenesis in zebrafish neurons, we show that biogenesis is normally balanced by mitophagy to maintain a constant mitochondrial population size. VapBP56S transgenics fail to increase mitophagy to compensate for the increase in mitochondrial biogenesis, suggesting an impaired mitophagic response. Finally, using a synthetic ER-mitochondria tether, we show that VapB's function in mitochondrial turnover is likely independent of ER-mitochondrial tethering by contact sites. Our findings demonstrate that VapB can control mitochondrial turnover in the axon terminal, and this function is altered by the P56S ALS-linked mutation.Significance statement Mitochondrial population dysfunction is tightly tied to neurodegenerative diseases, including ALS. Maintenance of the mitochondrial population in neurons requires the birth of new mitochondria and the degradation of damaged organelles. ER-mitochondrial contact site proteins are in a position to regulate both processes in neurons. Our work demonstrates that an ALS-associated mutation in the contact site protein VapB disrupts both processes, identifying VapB as a mediator of regulated mitochondrial turnover to maintain a steady-state mitochondrial population.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping