Parkinson’s damage starts at the synapse, years before symptoms
In Parkinson’s disease, nerve cells die in a brain region that controls movement. But the damage begins far earlier, at the junctions where neurons communicate. New research identifies a key protein involved.
Parkinson’s disease involves the gradual loss of dopamine-producing neurons in the brainstem. Motor symptoms, including stiffness, tremor, and slowed movement, typically appear only after a large proportion of these neurons are already gone. Mounting evidence suggests the trouble starts years earlier at synapses: the connection points where neurons communicate.
An international study published in eLife investigated the role of the protein LRRK2, which is genetically strongly linked to Parkinson’s. The researchers combined literature meta-analysis, protein measurements, and electrophysiological recordings in mouse models and in human neurons derived from stem cells.
LRRK2 reshapes the actin network at synapses
The study found that BDNF, a growth signal that helps neurons survive and form connections, activates LRRK2. Once activated, LRRK2 interacts with proteins that build the cytoskeleton, the internal support framework of a cell, specifically actin at the synapse. When LRRK2 is absent or dysfunctional, synaptic architecture changes and BDNF signalling is impaired.
In young mice lacking LRRK2, the researchers observed structural changes in neuronal extensions called dendrites. Notably, this effect was partially normalised in older mice, suggesting the problem is most prominent early in development.
Implications for treatment
The idea that synaptic damage precedes Parkinson’s is not new. But LRRK2’s specific role in the actin network offers a more concrete target for drug development. LRRK2 inhibitors are already being explored in clinical trials. Whether targeting actin dynamics via LRRK2 can prevent early damage in people remains to be shown.
The study is relevant to the question of early intervention in people with genetic risk. Not everyone carrying a LRRK2 mutation develops Parkinson’s, but risk is elevated. Whether synaptic biomarkers could eventually predict who will develop disease requires further research.
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