ArticleNPJ Parkinson's disease2023
The small GTPase Rit2 modulates LRRK2 kinase activity, is required for lysosomal function and protects against alpha-synuclein neuropathology.
Article in NPJ Parkinson's disease, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 25 citations in OpenAlex.
- Genetic architecture and molecular pathogenesis of Parkinson's disease: emerging mechanisms and therapeutic targets.Metabolic brain disease · 2026Review
- Cell Death in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets.MedComm · 2026Review
- Multiple system atrophy: advances in pathogenesis and emerging therapeutic strategies.Journal of neurology · 2025Review
- The genetic architecture of cervical length is shared with spontaneous preterm birth risk.Communications medicine · 2025Article
- Genomic and molecular evidence that the LncRNA DSP-AS1 modulates desmoplakin expression.Human genetics · 2025Article
- Clinical progression and genetic pathways in body-first and brain-first Parkinson's disease.Molecular neurodegeneration · 2025Article
- Prioritizing Parkinson's disease risk genes in genome-wide association loci.NPJ Parkinson's disease · 2025Article
- New Multiomic Studies Shed Light on Cellular Diversity and Neuronal Susceptibility in Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2025Review
- Canonical and noncanonical autophagy: involvement in Parkinson's disease.Frontiers in cell and developmental biology · 2025Review
- Mitochondrial Dysfunction in Parkinson's Disease: A Contribution to Cognitive Impairment?International journal of molecular sciences · 2024Review
- Key genes and convergent pathogenic mechanisms in Parkinson disease.Nature reviews. Neuroscience · 2024Review
- Silencing Parkinson's risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viability.NPJ Parkinson's disease · 2024Article
- Unraveling the Genetic Landscape of Neurological Disorders: Insights into Pathogenesis, Techniques for Variant Identification, and Therapeutic Approaches.International journal of molecular sciences · 2024Review
- Rit2 silencing in dopamine neurons drives a Parkinsonian phenotype.bioRxiv : the preprint server for biology · 2023Article
- Selective dopaminergic vulnerability in Parkinson's disease: new insights into the role of DAT.Frontiers in neuroscience · 2023Review
- Measurement of LRRK2 Kinase Activity by Proximity Ligation Assay.Bio-protocol · 2021Article
- A pH-eQTL Interaction at theFrontiers in aging neuroscience · 2021Article
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Authors and funding
13 authors at 3 institutions in 3 countries.
Funding
Abstract
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.
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Registered trials
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