Rab32-KO Mouse

Rab32, a member of the Rab small GTPase family, is a key regulator in multiple cellular processes. It is involved in membrane trafficking pathways, especially in endosomal trafficking, and plays important roles in the biogenesis of lysosome-related organelles and host defense against certain pathogenic microbial infections [4].

In glioblastoma multiforme (GBM), Rab32 is significantly elevated, especially in the mesenchymal subtype, and is positively correlated with tumor grade and poor prognosis. Knockdown of Rab32 attenuated GBM migration and invasion, suppressed invasion-related proteins and mesenchymal transition markers. It was found to regulate ERK1/2/Drp1-dependent mitochondrial fission and mesenchymal transition to promote GBM aggressiveness [1].

In the context of intracellular bacterial pathogens, Rab32 and its guanine nucleotide exchange factor BLOC-3 are essential to prevent the growth of Salmonella enterica serovar Typhi in mice, and Rab32 also controls infection by Listeria monocytogenes [2].

In Parkinson's disease, the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in multiple families. Functional studies showed that RAB32 Arg71 activates LRRK2 kinase more than RAB32 Ser71, indicating it as a novel genetic risk factor [3,5].

In rats with peripheral nerve injury, Rab32 facilitates Schwann cell pyroptosis by elevating ROS levels, and silencing Rab32 attenuated this pyroptosis and promoted peripheral nerve regeneration [6].

In summary, Rab32 is crucial in diverse biological processes such as tumor cell migration, host defense against bacteria, and neuronal-related pathologies. The use of gene-knockdown models in different disease contexts has revealed its role in promoting or suppressing disease-related cellular events, providing potential therapeutic targets for GBM, intracellular bacterial infections, Parkinson's disease, and peripheral nerve injuries.

References:

1. Chen, Pin, Lu, Yanbing, He, Binfeng, Huang, Wei, Zhang, Xiaobiao. 2023. Rab32 promotes glioblastoma migration and invasion via regulation of ERK/Drp1-mediated mitochondrial fission. In Cell death & disease, 14, 198. doi:10.1038/s41419-023-05721-3. https://pubmed.ncbi.nlm.nih.gov/36922509/

2. Solano-Collado, Virtu, Rofe, Adam, Spanò, Stefania. 2016. Rab32 restriction of intracellular bacterial pathogens. In Small GTPases, 9, 216-223. doi:10.1080/21541248.2016.1219207. https://pubmed.ncbi.nlm.nih.gov/27645564/

3. Gustavsson, Emil K, Follett, Jordan, Trinh, Joanne, Alessi, Dario R, Farrer, Matthew J. 2024. RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses. In The Lancet. Neurology, 23, 603-614. doi:10.1016/S1474-4422(24)00121-2. https://pubmed.ncbi.nlm.nih.gov/38614108/

4. Ohbayashi, Norihiko, Fukuda, Mitsunori, Kanaho, Yasunori. . Rab32 subfamily small GTPases: pleiotropic Rabs in endosomal trafficking. In Journal of biochemistry, 162, 65-71. doi:10.1093/jb/mvx027. https://pubmed.ncbi.nlm.nih.gov/28430987/

5. Hop, Paul J, Lai, Dongbing, Keagle, Pamela J, Kenna, Kevin P, Landers, John E. 2024. Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease. In Nature genetics, 56, 1371-1376. doi:10.1038/s41588-024-01787-7. https://pubmed.ncbi.nlm.nih.gov/38858457/

6. Wang, Jiayi, Chen, Pin, Han, Guanjie, He, Binfeng, Lu, Shunyi. 2024. Rab32 facilitates Schwann cell pyroptosis in rats following peripheral nerve injury by elevating ROS levels. In Journal of translational medicine, 22, 194. doi:10.1186/s12967-024-04999-x. https://pubmed.ncbi.nlm.nih.gov/38388913/