Dystrophic changes of nigrostriatal axons harboring a Synj1 Parkinson mutation suggest catastrophic failure of endocytic mechanisms
- 1Departments of Neuroscience and of Cell Biology, Program in Cellular Neuroscience, Neurodegeneration, and Repair, Howard Hughes Medical Institute, Yale School o
Abstract
Synaptojanin 1 is a brain enriched phosphoinositide phosphatase implicated in endocytosis at the synapse. A mutation (R258Q) that selectively impairs its Sac1 phosphatase domain causes early onset familial Parkinsonism. Neurons of mice with this mutation display synaptic vesicle traffic defects across the brain, but selective dystrophic changes in a subset of dopaminergic axons in the dorsolateral striatum. Using correlative light microscopy-FIB-SEM of mutant mouse striata to visualize in 3D these abnormal structures we show that they represent clusters of focal axonal dilations harboring massive, onion-like DAT enriched plasma membrane infoldings, generally localized next to cell bodies of neighboring cells, often engulfing evaginations of such cells. This dysmorphia was associated with a deficit in dopamine release in the same striatal region. Given the involvement of Synj1 in endocytic mechanisms, these structures may reflect an imbalance between exocytosis and endocytosis. Their occurrence only in a subset of axons suggest a vulnerability threshold of these axons beyond which the expansion of the plasma membrane is not counteracted by compensatory mechanisms.
Related
- Generation of an induced pluripotent stem cell line, LCSBi021-A, from a Parkinson's disease patient harboring the missense mutation c.213C>G (p.Ser71Arg) in the RAB32 gene
- EEG in Parkinson’s Disease: Mechanisms, Biomarkers and Translational Opportunities
- Levodopa induced dyskinesia severity is linked to distinct microstructural alterations in nigrostriatal and brainwide neural circuits
- The impact of alpha synuclein overexpression on nigrostriatal transmission
- Synonymous COL7A1 c.6846G>C in Dystrophic Epidermolysis Bullosa: Oral Phenotypic Expansion and Palatal Ultrastructure
BibTeX
@misc{wu2026dystrophic,
title = {{Dystrophic changes of nigrostriatal axons harboring a Synj1 Parkinson mutation suggest catastrophic failure of endocytic mechanisms}},
author = {Y. Wu and P. Xu and J. Moran and C. S. Xu and K. Hayworth and M. Cao and L. Shao and D. J. Surmeier and H. Hess and P. De Camilli},
howpublished = {bioRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.24.733515},
url = {https://www.biorxiv.org/content/10.64898/2026.06.24.733515v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Dystrophic changes of nigrostriatal axons harboring a Synj1 Parkinson mutation suggest catastrophic failure of endocytic mechanisms
AU - Y. Wu
AU - P. Xu
AU - J. Moran
AU - C. S. Xu
AU - K. Hayworth
AU - M. Cao
AU - L. Shao
AU - D. J. Surmeier
AU - H. Hess
AU - P. De Camilli
PY - 2026
DA - 2026/06/24
PB - bioRxiv
DO - 10.64898/2026.06.24.733515
UR - https://www.biorxiv.org/content/10.64898/2026.06.24.733515v2
AB - Synaptojanin 1 is a brain enriched phosphoinositide phosphatase implicated in endocytosis at the synapse. A mutation (R258Q) that selectively impairs its Sac1 phosphatase domain causes early onset familial Parkinsonism. Neurons of mice with this mutation display synaptic vesicle traffic defects across the brain, but selective dystrophic changes in a subset of dopaminergic axons in the dorsolateral striatum. Using correlative light microscopy-FIB-SEM of mutant mouse striata to visualize in 3D these abnormal structures we show that they represent clusters of focal axonal dilations harboring massive, onion-like DAT enriched plasma membrane infoldings, generally localized next to cell bodies of neighboring cells, often engulfing evaginations of such cells. This dysmorphia was associated with a deficit in dopamine release in the same striatal region. Given the involvement of Synj1 in endocytic mechanisms, these structures may reflect an imbalance between exocytosis and endocytosis. Their occurrence only in a subset of axons suggest a vulnerability threshold of these axons beyond which the expansion of the plasma membrane is not counteracted by compensatory mechanisms.
ER -