Researchers at NIMHANS, Bengaluru have shed new light on early molecular events that may trigger Parkinson’s Disease (PD), proposing a shift from conventional theory that has guided drug development for decades.
Their study has suggested that disease-specific chemical changes in α-Synuclein (αSyn) — a protein strongly linked to Parkinson’s — may promote the trapping of various cellular proteins, seeding the formation of Lewy bodies (protein deposits in the brain’s nerve cells) much before visible protein aggregates appear. Lewy bodies are a pathological hallmark of PD and related disorders 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 scholar, as lead author, the study has been published in Communications Biology (Nature portfolio) on January 8. It was carried out 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, is characterised by the loss of dopamine-producing neurons and the accumulation of αSyn-rich inclusions. For decades now, scientific efforts have focused on blocking αSyn aggregation into fibrils, assumed to be the primary driver of the disease. However, drugs designed on this principle have repeatedly failed in clinical trials.
“Our findings suggest that early, disease-specific mis-interactions of αSyn monomers may be key events that initiate Lewy body assembly,” said Dr. Sivaraman, noting that modifying the therapeutic focus could open up new avenues to treating the condition.
The team of researchers examined two Parkinson’s-linked post-translational modifications commonly found in diseased brain tissue — C-terminal truncation (ΔC) and serine-129 phosphorylation (pS129). These modifications change the protein’s charge and structure, exposing sticky regions that encourage unintended protein binding. Using biophysical assays, the researchers observed that modified αSyn showed broad and promiscuous binding with unrelated cellular proteins, unlike the more specific interactions seen with the normal variant, behaving 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, potentially explaining Lewy body nucleation and growth. Previous ultrastructural studies showing truncated αSyn in Lewy body cores and phosphorylated αSyn at the periphery support this view.
“This opens up a new dimension. Instead of focusing only on fibrillization properties, therapies should also aim to prevent abnormal binding behaviour of disease-modified αSyn variants,” Dr. Sivaraman said.
Why this matters
In India’s rapidly ageing population, Parkinson’s Disease is a cause of significant concern. Not only is the disease expected to rise with the increase in the elderly population, there is also a growing tide of early-onset Parkinson’s disease.
In India, the average age of diagnosis is 51, nearly 10 years earlier than the global average of 60, and together this could mean a significant burden of the disease in the near future, making research into therapeutic efforts in this direction, crucial.
Stating that the findings offer fresh clues on how Parkinson’s may begin at the cellular level, the doctor said the study explains how chemical changes in αSyn can turn a normal protein into one that sticks to and traps other proteins, possibly setting off Lewy body formation. The work also brings together biophysics and brain pathology to explain a long-standing puzzle about how these disease structures originate.
Researchers said such early changes could be better targets for future drugs, allowing intervention before irreversible nerve cell damage sets in. The study adds to NIMHANS’ growing body of work on 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 – January 17, 2026 06:00 am IST
