Rit2 protein clears toxic alpha-synuclein clumps from nerve cells
Current treatments increase dopamine, but don't alter Parkinson's progression
The Rit2 protein clears toxic forms of the alpha-synuclein protein from nerve cells, where it manifests as a hallmark symptom of Parkinson’s disease, a study reveals.
Targeting Rit2 could represent an effective strategy to combat nerve cell loss in familial and sporadic forms of the disease, its researchers noted.
“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,” study co-lead Mattia Volta, PhD, a neuroscientist at the Institute for Biomedicine, Eurac Research in Bolzano, Italy, said in a news release.
The study, “The small GTPase Rit2 modulates LRRK2 kinase activity, is required for lysosomal function and protects against alpha-synuclein neuropathology,” was published in npj Parkinson’s Disease.
In Parkinson’s, toxic clumps of alpha-synuclein are thought to contribute to the progressive loss of dopaminergic neurons, the nerve cells in the brain that produce the signaling molecule dopamine. Eventually, dopamine levels become abnormally low, triggering the onset of motor symptoms.
Current treatments are primarily designed to ease motor symptoms by increasing dopamine, but they’re unable to affect alpha-synuclein aggregation or alter the disease’s progression.
“Unfortunately, at this stage, no treatment is available, we can only alleviate the symptoms,” Volta said. “Therefore, anything that helps prevent and detect the disease at an early stage is crucial.”
Most cases of Parkinson’s are sporadic and are caused by a combination of genetic and environmental factors. Among the genetic mutations associated with Parkinson’s, those in the LRRK2 gene have been linked to both familial and sporadic Parkinson’s.
Several reports indicate mutant LRRK2 impairs autophagy, a tightly regulated process that’s responsible for degrading cellular waste, including aggregated proteins. Dopaminergic neurons with impaired autophagy may not be able to properly clear alpha-synuclein clumps, resulting in toxic buildup and cell death.
Parkinson’s risk has also been connected to variants in the RIT2 gene, causing a deficiency of an enzyme involved in nerve cell function (Rit2). Because both Rit2 and LRRK2 work through the same signaling pathway, researchers in Italy, collaborating with scientists in Canada, hypothesized a connection was shared via autophagy.
Targeting the Rit2 protein
Initial experiments confirmed the activity of the RIT2 gene was 2.2 times lower in dopaminergic neurons isolated from sporadic Parkinson’s patients.
Similar results were seen in cells carrying an LRRK2 mutation called G2019S, the most common genetic cause of Parkinson’s, suggesting “a possible role for Rit2 in both familial and [sporadic Parkinson’s disease] biology,” the researchers wrote.
G2019S-LRRK2 cells were marked by functional and structural defects in lysosomes, the cellular components where autophagic degradation takes place. Overproducing Rit2 rescued these defects and reduced toxic alpha-synuclein clumps without affecting healthy cells or total alpha-synuclein and LRRK2 levels.
“First, we saw in tests how the accumulation of alpha-synuclein became less when we increased the expression of the RIT2 gene,” Volta said.
The G2019S disease-causing mutation is known to increase the activity of the LRRK2 enzyme three to four times. Researchers discovered Rit2 directly interacted with and decreased the activity of G2019S-LRRK2 in the cell.
The effects of Rit2 expression were then tested in a Parkinson’s mouse model. The mice were modified to form damaging alpha-synuclein clumps in dopaminergic neurons, triggering motor symptoms.
Co-expressing Rit2 in the brain greatly weakened the loss of dopaminergic neurons, significantly preserved mature neurons, reduced alpha-synuclein clumps, and suppressed LRRK2’s over-activation. Over-expressing Rit2 also strongly promoted motor activity in mice.
“There we saw that increasing the expression of RIT2 protected neurons from the accumulation of pathological alpha-synuclein and cell death,” Volta said. “This also confirmed our results in a complete and complex organism.”
Cells lacking Rit2 showed similar defects in G2019S-LRRK2 cells, indicating “the loss of Rit2 affects [autophagy] functionality and is required for lysosome activity,” the researchers noted.
Volta said researchers then removed the gene and saw the “cell actually lost control over processes that keep proteins, including alpha-synuclein, in check.”
“We demonstrate that Rit2 acts both on autophagy-related processes and [alpha-synuclein] clearance,” the researchers concluded. “Our results suggest Rit2, through modulation of LRRK2 activity, as a novel target for neuroprotection in [Parkinson’s disease] and a modulator of [autophagy].”
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