Rit2, or Ras-like without CAAX2, is a member of the Ras superfamily. Its protein product plays important roles in vital cellular functions such as differentiation and survival [1]. It has been implicated in pathways related to the autophagy-lysosomal pathway (ALP) [4]. The gene is of great biological importance as it has been associated with several neurological and psychiatric disorders [1]. Genetic models, especially KO/CKO mouse models, have been crucial in studying Rit2.

In KO mouse models, conditional Rit2 silencing in dopamine neurons led to a progressive motor dysfunction, more rapid in males than females [2,3,5]. This was accompanied by decreases in DA release, striatal DA content, phenotypic DAergic markers, and loss of DA neurons, along with increased pSer129-alpha synuclein expression [2,3,5]. These findings suggest that Rit2 loss is causal for substantia nigra pars compacta (SNc) cell death and a Parkinson-like phenotype, revealing sex-specific differences in response to Rit2 loss [2,3,5].

In conclusion, Rit2 is essential for normal cellular functions and is intricately involved in maintaining dopamine neuron viability and motor function. The Rit2 KO/CKO mouse models have significantly contributed to understanding its role in Parkinson's disease, highlighting its importance in the context of this neurodegenerative disorder [2,3,5].

References:

1. Daneshmandpour, Yousef, Darvish, Hossein, Emamalizadeh, Babak. 2018. RIT2: responsible and susceptible gene for neurological and psychiatric disorders. In Molecular genetics and genomics : MGG, 293, 785-792. doi:10.1007/s00438-018-1451-4. https://pubmed.ncbi.nlm.nih.gov/29860660/

2. Kearney, Patrick J, Zhang, Yuanxi, Tan, Yanglan, Yue, Zhenyu, Melikian, Haley E. 2023. Rit2 silencing in dopamine neurons drives a progressive Parkinsonian phenotype. In Research square, , . doi:10.21203/rs.3.rs-2944614/v1. https://pubmed.ncbi.nlm.nih.gov/37293098/

3. Kearney, Patrick J, Zhang, Yuanxi, Tan, Yanglan, Yue, Zhenyu, Melikian, Haley E. 2023. Rit2 silencing in dopamine neurons drives a Parkinsonian phenotype. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.04.26.538430. https://pubmed.ncbi.nlm.nih.gov/37162843/

4. Gao, Andy Y L, Montagna, Daniel R, Hirst, Warren D, Temkin, Paul A. 2024. RIT2 regulates autophagy lysosomal pathway induction and protects against α-synuclein pathology in a cellular model of Parkinson's disease. In Neurobiology of disease, 199, 106568. doi:10.1016/j.nbd.2024.106568. https://pubmed.ncbi.nlm.nih.gov/38885848/

5. Kearney, Patrick J, Zhang, Yuanxi, Liang, Marianna, Yue, Zhenyu, Melikian, Haley E. 2024. Silencing Parkinson's risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viability. In NPJ Parkinson's disease, 10, 41. doi:10.1038/s41531-024-00648-8. https://pubmed.ncbi.nlm.nih.gov/38395968/