Axonal dysfunction precedes axonal degeneration in a mouse model of progressive parkinsonism
- 1Cellular Neurophysiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Abstract
Axons of substantia nigra dopaminergic neurons "die back" in Parkinson's disease (PD), exhibiting early degeneration relative to cell bodies, a key feature also observed in PD models. A critical step towards understanding the process of axonal neurodegeneration is to determine the physiological properties of dopaminergic axons that are altered during the early stages of cellular dysfunction. Here, we compared the electrophysiology and calcium dynamics of dopaminergic axons in the MitoPark model of PD with age-matched controls. Our experiments show a pronounced reduction in action potential (AP)-evoked calcium signals in MitoPark axons that emerges well before the onset of dopaminergic fiber loss and motor deficits. In addition, calcium imaging and direct axon recording revealed deficits in AP propagation accompanied by alterations in the axonal AP waveform. Therefore, our experimental findings identify the progression of axon-specific physiological deficits that occur long before neurodegeneration, more precisely defining the period that precedes axonal loss.
Related
- Emergence of Task-Related Motor Cortical Dysfunction in Mice with Progressive Parkinsonism
- Axonal Branch Points of Parvalbumin Interneurons are Focal Sites of Tau-Induced Degeneration
- Genetic ablation of Sarm1 attenuates axonal degeneration in a mouse model of CMT2J
- Abca4 Knockdown in the Cone-Rich Rodent Psammomys Obesus Leads to Stargardt's Disease-Like Progressive Retinal Degeneration
- Free Mitochondrial DNA and Mitophagy Dysfunction in Diabetic Kidney Disease: A Central Mitochondrial-Inflammatory Axis Driving Progressive Renal Injury.
BibTeX
@misc{lipkin2026axonal,
title = {{Axonal dysfunction precedes axonal degeneration in a mouse model of progressive parkinsonism}},
author = {A. M. Lipkin and A. Boronat-Garcia and N. L. O'Prey and R. Zhang and Z. M. Khaliq},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.755486},
url = {https://www.biorxiv.org/content/10.64898/2026.09.29.755486v1},
note = {CC0},
}
RIS
TY - UNPB
TI - Axonal dysfunction precedes axonal degeneration in a mouse model of progressive parkinsonism
AU - A. M. Lipkin
AU - A. Boronat-Garcia
AU - N. L. O'Prey
AU - R. Zhang
AU - Z. M. Khaliq
PY - 2026
DA - 2026/09/29
PB - bioRxiv
DO - 10.64898/2026.09.29.755486
UR - https://www.biorxiv.org/content/10.64898/2026.09.29.755486v1
AB - Axons of substantia nigra dopaminergic neurons "die back" in Parkinson's disease (PD), exhibiting early degeneration relative to cell bodies, a key feature also observed in PD models. A critical step towards understanding the process of axonal neurodegeneration is to determine the physiological properties of dopaminergic axons that are altered during the early stages of cellular dysfunction. Here, we compared the electrophysiology and calcium dynamics of dopaminergic axons in the MitoPark model of PD with age-matched controls. Our experiments show a pronounced reduction in action potential (AP)-evoked calcium signals in MitoPark axons that emerges well before the onset of dopaminergic fiber loss and motor deficits. In addition, calcium imaging and direct axon recording revealed deficits in AP propagation accompanied by alterations in the axonal AP waveform. Therefore, our experimental findings identify the progression of axon-specific physiological deficits that occur long before neurodegeneration, more precisely defining the period that precedes axonal loss.
ER -