NIMHANS study proposes new model for early protein deposit formation in Parkinson’s disease
Researchers at NIMHANS, Bengaluru, have shed new light on the early molecular events that may trigger Parkinson’s Disease (PD), proposing a shift from the traditional theory that has guided drug development for decades.
Their work 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 and trigger 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 disease 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 PhD student Sneha Jos as the lead author. study published in Communication Biology (Nature portfolio) on January 8th. 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 disease after Alzheimer’s, is characterized by the loss of dopamine-producing neurons and the accumulation of αSyn-rich residues. For decades, scientific efforts have focused on preventing αSyn, the presumed primary driver of disease, from aggregating into fibrils. But drugs designed according to 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. Changing the therapeutic focus may open up new ways to treat the condition, Sivaraman noted.
The research team examined two Parkinson-related post-translational modifications commonly found in diseased brain tissue: C-terminal truncation (ΔC) and serine-129 phosphorylation (pS129). These modifications change the charge and structure of the protein, exposing sticky regions that promote undesirable protein binding. Using biophysical analyses, the researchers observed that modified αSyn showed broad and promiscuous binding with unrelated cellular proteins, in contrast to the more specific interactions seen in the normal variant, which act as molecular ‘glues’.
Based on these observations, the authors proposed that disease-altered αSyn monomers may serve as scaffolds that assemble various proteins and organelles into dense clusters, potentially explaining Lewy body nucleation and growth. Previous ultrastructural studies showing truncated αSyn in Lewy body nuclei and phosphorylated αSyn in the periphery support this view.
“This opens a new dimension. Rather than focusing solely on fibrillization properties, therapies should also aim to prevent the abnormal binding behavior of disease-altered αSyn variants,” Sivaraman said.
Why is this important?
Parkinson’s Disease is a major concern in India’s rapidly aging population. In addition to the fact that the disease is expected to increase with the increase in the elderly population, early-onset Parkinson’s disease is also on the rise.
The average age at diagnosis in India is 51 years, almost 10 years earlier than the global average of 60, which could mean a significant burden of the disease in the near future, making research into therapeutic efforts in this direction vital.
Stating that the findings provide new clues about how Parkinson’s disease may begin at the cellular level, the doctor said that the study explains how chemical changes in αSyn can transform a normal protein into one that adheres to and traps other proteins, possibly triggering the formation of Lewy bodies. The study also brings together biophysics and brain pathology to explain a long-standing puzzle about how these disease structures arise.
Such early changes could be better targets for future drugs, allowing intervention before irreversible nerve cell damage occurs, the researchers said. The study adds to the growing body of work on αSyn biology, including recent findings on the nuclear role of NIMHANS as a histone chaperone, and positions the institute at the forefront of mechanistic Parkinson’s research.
It was published – 17 January 2026 06:00 IST
