Summary: Researchers identified a protein that could play a significant role in preventing Parkinson’s disease. The protein, linked to the RIT2 gene, is believed to control the accumulation of alpha-synuclein, which destroys neuronal cells and is a known indicator of the disease.
Experiments conducted in cell models and on mice showed that increasing the expression of the RIT2 gene helped protect neurons from damage caused by alpha-synuclein. While the research is in its early stages, it opens up a new approach to preventing Parkinson’s disease by regulating the RIT2 gene.
Key Facts:
- The research identified a protein linked to the RIT2 gene that controls the accumulation of alpha-synuclein, which destroys neuronal cells and is a key factor in Parkinson’s disease.
- Experiments on cell models and mice demonstrated that increasing the expression of the RIT2 gene can protect neurons from the damaging accumulation of alpha-synuclein.
- Although the research is at the genetic level currently, it holds promise for a simpler method to regulate the RIT2 gene, potentially reducing Parkinson’s risk for many people.
Source: Eurac Research
Parkinson’s disease is the second most common neurodegenerative disease in the world, affecting two to three percent of people over the age of 60. In the Western world, the number is likely to increase due to the aging population, with major social burdens and costs for healthcare systems.
“Unfortunately, at this stage, no treatment is available, we can only alleviate the symptoms. Therefore, anything that helps prevent and detect the disease at an early stage is crucial,” explains Mattia Volta, neuroscientist at Eurac Research.
“We have now identified a new so-called molecular target – a protein involved in the typical processes of the disease – which we can interfere with to reduce the risk of disease.”
It has long been known that in the brains of those who become ill, accumulations of the protein alpha-synuclein develop, which intoxicate and eventually kill neuronal cells.
The causes of these accumulations are diverse and not all are yet known. In some cases, there are heritable and known genetic mutations, but risk factors that affect a larger portion of the population are still insufficiently studied.
With their research, Volta and his colleagues were able to demonstrate that the accumulation of alpha-synuclein is also related to the expression of the RIT2 gene.
“First, we saw in tests how the deposition of alpha-synuclein became less when we increased the expression of the RIT2 gene,” Volta explains.
“Then, as counterevidence, we removed the gene and saw that the cell actually lost control over processes that keep proteins, including alpha-synuclein, in check. In Bolzano, we did experiments on cell models, and in Canada, our colleagues worked with mice.
“There we saw that increasing the expression of RIT2 protected neurons from the accumulation of pathological alpha-synuclein and cell death. This also confirmed our results in a complete and complex organism.”
So far, these are interventions at the genetic level, but the research teams are confident that in the future a simpler system can be developed to operate on the RIT2 gene.
If regulatory intervention could be made in all those found to have decreased expression of the RIT2 gene, it would reduce the risk of Parkinson’s disease for many people.
The study was recently published in Nature Group’s journal NPJ Parkinson’s Disease and involved close collaboration between Eurac Research’s Institute of Biomedicine and Laval University in Quebec City.
The first author of the scientific paper is Julia Obergasteiger, formerly a doctoral student in Bolzano and now working at the Canadian university with a research grant won on a competitive basis.
About this genetics and Parkinson’s disease research news
Author: Valentina Bergonzi
Source: Eurac Research
Contact: Valentina Bergonzi – Eurac Research
Image: The image is credited to 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 (PD) misfolded alpha-synuclein (aSyn) accumulates in the substantia nigra, where dopaminergic neurons are progressively lost.
The mechanisms underlying aSyn pathology are still unclear, but they are hypothesized to involve the autophagy-lysosome pathway (ALP). LRRK2 mutations are a major cause of familial and sporadic PD, and LRRK2 kinase activity has been shown to be involved in pS129-aSyn inclusion modulation.
We observed selective downregulation of the novel PD risk factor RIT2 in vitro and in vivo. Rit2 overexpression in G2019S-LRRK2 cells rescued ALP abnormalities and diminished aSyn inclusions.
In vivo, viral mediated overexpression of Rit2 operated neuroprotection against AAV-A53T-aSyn. Furthermore, Rit2 overexpression prevented the A53T-aSyn-dependent increase of LRRK2 kinase activity in vivo.
On the other hand, reduction of Rit2 levels leads to defects in the ALP, similar to those induced by the G2019S-LRRK2 mutation.
Our data indicate that Rit2 is required for correct lysosome function, inhibits overactive LRRK2 to ameliorate ALP impairment, and counteracts aSyn aggregation and related deficits.
Targeting Rit2 could represent an effective strategy to combat neuropathology in familial and idiopathic PD.
