Summary: Researchers have identified a protein connected to the RIT2 gene that appears to play a key role in regulating the accumulation of alpha-synuclein, the toxic protein that damages and kills neurons and is a hallmark of Parkinson’s disease. Early laboratory and animal studies suggest boosting RIT2 expression can reduce harmful alpha-synuclein buildup and protect neuronal cells, pointing to a potential new preventive strategy for Parkinson’s.
In cell-based experiments and in mouse models, increasing RIT2 expression decreased alpha-synuclein deposition and improved markers of neuronal health. Conversely, removing or reducing RIT2 impaired cellular systems that normally control protein quality, leading to greater accumulation of pathological alpha-synuclein. These results indicate RIT2 helps maintain protein clearance pathways and can limit processes that contribute to Parkinson’s neuropathology.
Key Facts:
- A protein linked to the RIT2 gene regulates accumulation of alpha-synuclein, the protein that damages neurons and is central to Parkinson’s disease pathology.
- Laboratory and mouse experiments showed that increasing RIT2 expression protects neurons from alpha-synuclein–related damage, while loss of RIT2 disrupts protein clearance mechanisms.
- Although current interventions target the gene itself in preclinical models, the findings support the idea that developing simpler, clinically applicable ways to modulate RIT2 could reduce Parkinson’s risk for many people.
Source: Eurac Research
Parkinson’s disease is the second most common neurodegenerative disorder worldwide, affecting about two to three percent of people over 60. As populations age in many regions, the number of affected individuals is expected to rise, increasing social and healthcare burdens. Because current medical options mainly relieve symptoms rather than halt or prevent the disease, new approaches that stop or slow disease development are urgently needed.
“At the moment we can only ease symptoms; we lack treatments that prevent Parkinson’s,” says Mattia Volta, neuroscientist at Eurac Research. “Identifying molecular targets involved early in disease processes gives us ways to interfere before irreversible neuron loss occurs.”
Decades of research have shown that alpha-synuclein aggregates form in the brains of people who develop Parkinson’s. These aggregates interfere with neuronal function and ultimately contribute to cell death. The causes of alpha-synuclein deposition are varied: some stem from rare genetic mutations, while other risk factors affecting broader populations remain incompletely understood.
Volta and colleagues showed that RIT2 expression influences alpha-synuclein handling in cells. “When we increased RIT2 expression, alpha-synuclein deposition declined,” Volta explains. “As a counter-check, removing RIT2 caused the cells to lose control of the mechanisms that keep proteins, including alpha-synuclein, in check.”
Experiments performed in Bolzano used cellular models, while collaborators in Canada tested effects in mice. In the animal studies, elevating RIT2 expression reduced alpha-synuclein–dependent neuronal damage and cell death, confirming that the protective effect can occur in a whole, living organism.
These interventions are currently implemented at the genetic level in preclinical research. The teams involved are optimistic that simpler, clinically feasible methods to modulate RIT2 activity or expression could be developed in the future. If people with lower RIT2 expression could be identified and given safe, effective ways to restore proper RIT2 function, it might lower their risk of developing Parkinson’s disease.
The study, published in the journal NPJ Parkinson’s Disease, is the result of a close collaboration between Eurac Research’s Institute of Biomedicine and Laval University in Quebec City. The paper’s first author is Julia Obergasteiger, who conducted doctoral research in Bolzano and now continues related work in Canada.
About this genetics and Parkinson’s disease research news
Author: Valentina Bergonzi ([email protected])
Source: Eurac Research
Contact: Valentina Bergonzi – Eurac Research
Image credit: Neuroscience News
Original Research: Open access. “The small GTPase Rit2 modulates LRRK2 kinase activity, is required for lysosomal function and protects against alpha-synuclein neuropathology” by Mattia Volta et al., NPJ Parkinson’s Disease.
Abstract
The small GTPase Rit2 modulates LRRK2 kinase activity, is required for lysosomal function and protects against alpha-synuclein neuropathology
In Parkinson’s disease, misfolded alpha-synuclein (aSyn) accumulates in the substantia nigra, leading to progressive loss of dopaminergic neurons. The mechanisms behind aSyn pathology remain incompletely understood, but impairment of the autophagy-lysosome pathway (ALP) is implicated. LRRK2 mutations contribute to familial and sporadic Parkinson’s, and LRRK2 kinase activity influences aSyn inclusion formation.
The researchers observed selective downregulation of the PD risk factor RIT2 both in vitro and in vivo. Overexpression of Rit2 in cells carrying the G2019S-LRRK2 mutation corrected ALP abnormalities and reduced aSyn inclusions. In vivo, viral-mediated Rit2 overexpression provided neuroprotection against AAV-A53T-aSyn and prevented the A53T-aSyn–dependent increase in LRRK2 kinase activity. Conversely, reducing Rit2 levels produced ALP defects similar to those caused by the G2019S-LRRK2 mutation.
These findings indicate Rit2 is required for normal lysosomal function, helps limit overactive LRRK2 signaling, improves ALP performance, and counters aSyn aggregation and related deficits. Targeting Rit2 may therefore offer a promising strategy to combat neuropathology in both familial and idiopathic Parkinson’s disease.