Axonal defects linked to rare form of Parkinson's disease

by Olivia Dimmer, Northwestern University

edited by Lisa Lock, reviewed by Robert Egan

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A genetic mutation linked to Parkinson's disease produced abnormalities in a subset of nerve cells, offering a clue about the disease's causes, according to a new study published in the Proceedings of the National Academy of Sciences. The findings offer new clues about how the neurodegenerative disorder begins and progresses, said D. James Surmeier, Ph.D., the Nathan Smith Davis professor and chair of neuroscience, who was a co-author of the study.

The research team focused on a mutation in the SYNJ1 gene, which has been shown to cause an early-onset inherited form of Parkinson's disease.

Parkinson's disease is characterized by the progressive loss of dopamine-producing neurons in the brain. Although mutations in SYNJ1 are rare, scientists often use inherited forms of Parkinson's as a window into understanding broader disease processes.

"Genetics provides an important window into disease mechanisms," Surmeier said. "In particular, genetic drivers of disease give us clues about why dopaminergic neurons are so vulnerable in PD. With that insight, we can design strategies to fix what goes wrong."

Swollen axons release less dopamine

Using advanced three-dimensional imaging and measurements in mice carrying the mutation, investigators found that parts of affected dopamine neurons called axons developed abnormal swelling and released less dopamine in the brain.

The abnormalities concentrated in axons that release dopamine in the dorsolateral striatum, a region known to be particularly vulnerable in Parkinson's disease. The swollen structures contained massive, onion-like folds of plasma membrane, suggesting that the normal process of recycling cellular membranes had broken down, Surmeier said.

"These neurons in humans are estimated to have a million transmitter release sites or more per axon," Surmeier said. "This very unusual design of the axon has long been thought to be a key factor in determining their vulnerability."

The study also found that while synaptic defects occurred more broadly, the dramatic axonal swelling appeared specifically in a subset of dopamine neurons. Other brain regions supplied by dopamine neurons did not show the same reductions in neurotransmitter release, Surmeier said.

Investigating energy failure at nerve endings

Looking ahead, Surmeier and his collaborators are now investigating whether deficits in energy production within dopamine neurons contribute to their degeneration. Surmeier said his team is particularly interested in understanding how these highly active nerve endings generate the energy required to sustain continuous neurotransmitter release.

"One of our longstanding hypotheses about pathogenesis in Parkinson's disease is that it stems largely from an acquired mitochondrial defect," Surmeier said. "There's a problem with energy generation. The power plants inside cells become dysfunctional."

To answer those questions, the team is developing advanced optical imaging tools capable of monitoring activity within the tiny axon terminals where dopamine release occurs.

"A key part of our effort is the development of genetically encoded optical probes targeted to the synaptic terminal, which will allow us to monitor biochemical processes there and to determine how they go awry in PD," Surmeier said. "It's a little bit like sending a probe to Mars."

Understanding why these neurons fail could ultimately point toward new strategies for slowing or preventing Parkinson's disease before significant neuronal loss occurs, Surmeier said.

Publication details

Yumei Wu et al., Dystrophic changes of nigrostriatal axons harboring a SYNJ1 Parkinson's mutation suggest catastrophic failure of endocytic mechanisms, Proceedings of the National Academy of Sciences (2026). DOI: 10.1073/pnas.2622215123

Journal information: Proceedings of the National Academy of Sciences

Key medical concepts

Dopaminergic Neurons

Clinical categories

NeurologyClinical genetics Provided by Northwestern University Who's behind this story?

Lisa Lock

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