PUBLICATION
Patient-specific mutation of a contact site protein Tomm70 causes neurodegeneration in a zebrafish model
- Authors
- Garg, V., Heinrich, R., Perera, R.P., Ischebeck, T., Möbius, W., Ruhwedel, T., Scholz, P., Salinas, G., Dullin, C., Göpfert, M.C., Engelmann, J., Dosch, R., Geurten, B.R.H.
- ID
- ZDB-PUB-250328-24
- Date
- 2025
- Source
- Disease models & mechanisms : (Journal)
- Registered Authors
- Dosch, Roland
- Keywords
- Endoplasmic reticulum-mitochondria contact site (ER-MCS), Neurodegeneration, Tomm70, Zebrafish
- MeSH Terms
-
- Dendrites/metabolism
- Dendrites/pathology
- Spinal Cord/pathology
- Spastic Paraplegia, Hereditary/genetics
- Spastic Paraplegia, Hereditary/pathology
- Zebrafish Proteins*/chemistry
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Mitochondrial Membrane Transport Proteins*/chemistry
- Mitochondrial Membrane Transport Proteins*/genetics
- Mitochondrial Membrane Transport Proteins*/metabolism
- Amino Acid Sequence
- Animals
- Endoplasmic Reticulum/metabolism
- Neurons/metabolism
- Neurons/pathology
- Neurodegenerative Diseases*/genetics
- Neurodegenerative Diseases*/pathology
- Mitochondrial Precursor Protein Import Complex Proteins
- Mitochondria/metabolism
- Membrane Transport Proteins*/genetics
- Membrane Transport Proteins*/metabolism
- Humans
- Nerve Degeneration*/genetics
- Nerve Degeneration*/pathology
- Zebrafish/genetics
- Zebrafish/metabolism
- Axons/metabolism
- Axons/pathology
- Mutation*/genetics
- Mutation, Missense/genetics
- PubMed
- 40151845 Full text @ Dis. Model. Mech.
Citation
Garg, V., Heinrich, R., Perera, R.P., Ischebeck, T., Möbius, W., Ruhwedel, T., Scholz, P., Salinas, G., Dullin, C., Göpfert, M.C., Engelmann, J., Dosch, R., Geurten, B.R.H. (2025) Patient-specific mutation of a contact site protein Tomm70 causes neurodegeneration in a zebrafish model. Disease models & mechanisms. :.
Abstract
Tomm70 is a receptor at the contact site between mitochondria and the endoplasmic reticulum, and has been identified as a risk gene for hereditary spastic paraplegia. Furthermore, de novo missense mutations in TOMM70 have been identified to cause neurological impairments in two unrelated patients. Here, we show that mutant zebrafish ruehreip25ca also harbor a missense mutation in tomm70, affecting the same conserved isoleucine residue as in one of the human patients. Using this model, we demonstrate how loss of Tomm70 function leads to impairment. At the molecular level, the mutation affects the interaction of Tomm70 with the endoplasmic reticulum protein Lam6, a known sterol transporter. At the neuronal level, the mutation impairs mitochondrial transport to the axons and dendrites, leading to demyelination of large calibre axons in the spinal cord. These neurodegenerative defects in zebrafish are associated with reduced endurance, swimming efficiency, and alterations in the C-start escape response, which correlate with decreased spiking in giant Mauthner neurons. Thus, in zebrafish, a mutation in the endoplasmic reticulum-mitochondria contact site protein Tomm70 recreates some of the neurodegenerative phenotypes characteristic of hereditary spastic paraplegia.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping