Their research has suggested that disease-specific chemical changes in α-Synuclein (αSyn) – a protein strongly linked to Parkinson’s disease – may promote the capture of various cellular proteins, promoting the formation of Lewy bodies (protein deposits in the brain’s nerve cells) long before visible protein aggregates appear. Lewy bodies are a pathological feature of Parkinson’s and related conditions such as dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA).
Led by Padavattan Sivaraman, Additional Professor in the Department of Biophysics, with Sneha Jos, a PhD researcher, as lead author, the study was published in Communication Biology (Nature portfolio) on January 8. It was conducted in collaboration with researchers from BRIC-inSTEM, MAHE-Bengaluru and CSIR-IMTECH, Chandigarh.
Beyond the ‘aggregation’ model
Parkinson’s, the second most common neurodegenerative disorder after Alzheimer’s disease, is characterized by the loss of dopamine-producing neurons and the accumulation of αSyn-rich inclusions. Scientific efforts have been focused for decades on blocking the aggregation of αSyn into fibrils, which is believed to be the main cause of the disease. However, drugs designed on this principle have repeatedly failed in clinical trials.
“Our findings suggest that early, disease-specific misinteractions of αSyn monomers may be key events that initiate Lewy body assembly,” said Dr. Sivaraman, noting that changing the therapeutic focus could open new avenues for treating the condition.
The team of researchers examined two Parkinson’s-related post-translational modifications commonly found in diseased brain tissue: C-terminal truncation (AC) and serine-129 phosphorylation (pS129). These modifications change the charge and structure of the protein, exposing sticky regions that promote unintended protein binding. Using biophysical assays, the researchers found that modified αSyn showed broad and promiscuous binding to unrelated cellular proteins, in contrast to the more specific interactions seen in the normal variant, which behaved like molecular “adhesives.”
Based on these observations, the authors proposed that disease-modified αSyn monomers may act as scaffolds that recruit diverse proteins and organelles into dense clusters, which could potentially explain the nucleation and growth of Lewy bodies. Previous ultrastructural studies showing truncated αSyn in Lewy body nuclei and phosphorylated αSyn at the periphery support this view.
“This opens up a new dimension. Instead of just focusing on the fibrillization properties, therapies should also aim to prevent abnormal binding behavior of disease-modified αSyn variants,” said Dr. Sivaraman.
Why this matters
In India’s rapidly aging population, Parkinson’s disease is of great concern. Not only is the disease expected to increase with the increase in the elderly population, there is also a growing number of cases of early Parkinson’s disease.
In India, the average age of diagnosis is 51 years, almost a decade earlier than the global average of 60 years. Together, this could represent a significant burden of the disease in the near future, making research into therapeutic efforts in this direction crucial.
The doctor claims that the findings provide new clues about how Parkinson’s disease can begin at the cellular level and that the study explains how chemical changes in αSyn can turn a normal protein into one that sticks to and holds other proteins, potentially causing the formation of Lewy bodies. The work also brings together biophysics and brain pathology to explain a long-standing puzzle about how these disease structures arise.
Researchers said such early changes could be better targets for future drugs, allowing intervention before irreversible damage to nerve cells occurs. The study adds to NIMHANS’ growing body of work in the field of αSyn biology, including recent findings on its nuclear role as a histone chaperone, positioning the institute at the forefront of mechanistic Parkinson’s research.
Published – Jan 17, 2026 06:00 IST
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