Bengaluru: Nimhans study questions long-held theory on Parkinson’s progression

Bengaluru: More than a century after Lewy bodies were first identified, their origin in Parkinson’s disease remains one of neuroscience’s enduring mysteries.

Now, new research from the National Institute of Mental Health and Neurosciences (Nimhans), Bengaluru, presents a model that could reshape how scientists understand and potentially treat the disease at an earlier stage.

Parkinson’s disease, the second most common neurological disorder after Alzheimer’s, affects millions worldwide. It is marked by tremors, muscle stiffness and slowed movement.

A key pathological feature is the presence of Lewy bodies — abnormal, protein-rich deposits inside brain cells. Since 1997, researchers have known that Lewy bodies are largely made up of a protein called alpha-synuclein. However, how these deposits form and why they contain hundreds of different cellular components remains unclear.

A study published in Communications Biology (Nature Portfolio) by Nimhans researchers reports that disease-specific changes in alpha-synuclein may act as the main early trigger for Lewy body formation.

Under normal conditions, alpha-synuclein is abundant in neurons and exists in a flexible, stable form, with its internal hydrophobic (“sticky”) region hidden. This enables normal cellular function.

The study shows that in Parkinson’s disease, alpha-synuclein undergoes structural changes that expose this sticky region. Once exposed, the protein behaves differently, binding indiscriminately to nearby cellular components instead of forming selective interactions.

“It essentially turns into a molecular trap,” Sneha Jos, the first author of the study, said, capturing other proteins, lipids and damaged organelles. This promiscuous behaviour helps explain why Lewy bodies are so complex — something traditional aggregation-focused models have struggled to explain.

"For decades, research centred on the idea that Lewy bodies form because alpha-synuclein aggregates into long fibrils, and many drug development efforts have targeted this process. Most have failed in clinical trials. Our study challenges this fibril-centric view, arguing that early, non-specific interactions, rather than aggregation alone, drive Lewy body formation," said Sivaraman Padavattan, Additional Professor, Department of Biophysics, Nimhans, who led the research.

Using biochemical and biophysical tests, the researchers showed that disease-linked forms of alpha-synuclein interact with many more cellular proteins than the normal form.

The team’s new 'Multifactorial Random Disorder Model' shifts attention to the earliest molecular events, opening avenues for biomarker development and therapy.

Intervening before alpha-synuclein turns into a cellular scavenger, the researchers suggest, could help slow or delay Parkinson’s disease before irreversible neuronal damage occurs.

The researchers are working to strengthen the study. "We are also planning to develop an early detection biomarker for Parkinson's in collaboration with Nimhans clinicians," added Padavattan.

Explaining the causes of Parkinson’s disease, he said the condition is broadly classified as familial and sporadic. The familial form, about 10–15% of cases, is linked to mutations in alpha-synuclein and related genes. Most patients fall under the sporadic category, with no single genetic cause identified.

Researchers have proposed several contributing factors for sporadic Parkinson’s, including environmental exposure.

Padavattan noted that certain herbicides, such as paraquat, commonly used in India, are particularly harmful. Such environmental factors, he said, are increasingly recognised as significant contributors to the disease.