Overlooked Parkinson’s variant harms Indian patients more, shows Nimhans study

Bengaluru: Patients with Parkinson’s disease in India could soon benefit from treatments that directly target the underlying cause of the condition, new research from the National Institute of Mental Health and Neuro Sciences (Nimhans) suggests.

The study, published in the international journal 'Cells' and led by Dr Indrani Datta of Nimhans, shows that the LRRK2 I1371V variant, found mainly in Indian and East Asian patients, causes more damage to brain cells than G2019S, the most studied Parkinson’s mutation globally.

This misclassification meant that despite clinicians observing severe motor symptoms, earlier disease onset, cognitive impairment, and poor response to standard therapies in patients carrying I1371V, the scientific community lacked cellular and molecular evidence to fully assess its impact.

Parkinson’s disease, a progressive disorder marked by the loss of dopamine-producing brain cells, mainly affects older adults.

Explaining the findings, Dr Indrani told DH that the LRRK2 I1371V mutation is not only disease-causing but, in several ways, causes more damage to brain cells than G2019S.

“The G2019S genetic mutation is prevalent among Caucasian and Ashkenazi Jewish populations, but is found in less than 0.1% of Indian patients or even East Asian patients,” said Dr Indrani.

Based on one study, the I1371V mutation found in Indians had been wrongly classified as non-pathogenic.

The team tested two LRRK2-targeting drugs on cells with the I1371V mutation. One, MLi-2, blocks the protein’s activity, while the other, GW5074, acts more broadly through multiple pathways.

GW5074 significantly outperformed MLi-2 in reversing membrane damage, restoring cholesterol levels, rebuilding cell surface architecture, and recovering dopamine transporter function.

This finding suggests that the I1371V mutation’s damage is driven mainly by a different part of the LRRK2 protein, its GTPase domain, rather than the kinase domain targeted by most existing drugs.

In simple terms, the drug that works for one variant of Parkinson’s may not work for another, Dr Indrani explained.

GTPases (guanosine triphosphatases) are enzymes that act as molecular switches in cells, while kinases facilitate the transfer of phosphate groups, playing a key role in cell signalling and regulation.

“Classifying I1371V as non-pathogenic based on a single study conducted in the wrong cell type had real consequences for how doctors and researchers understood the disease in patients who carry it,” she said.