Rab29 is a Rab guanosine triphosphatase encoded in the PARK16 locus. It is involved in multiple membrane trafficking processes and is a key regulator in the activation of leucine-rich repeat kinase 2 (LRRK2) [1,2,4]. Mutations in LRRK2 are a common genetic cause of late-onset Parkinson's disease, indicating the importance of Rab29 in Parkinson's disease-related pathways [1].

In gene knockout studies, knocking out Rab29 in A549 cells reduces endogenous LRRK2-mediated phosphorylation of Rab10, suggesting its role in LRRK2-regulated phosphorylation events [4]. However, in wild-type LRRK2, LRRK2[R1441C] or VPS35[D620N] knock-in mouse tissues and primary cell lines, knockout of Rab29 does not influence endogenous LRRK2 activity based on the assessment of Rab10 and Rab12 phosphorylation [3]. Also, in a combined knockout mouse model of Lrrk2 and Rab29, only 18-24-month Rab29-/-and double (Lrrk2-/-/Rab29-/-) knockout mice had diminished locomotor behavior in open field compared to wild-type mice, with no differences in PD-like pathology [5].

In conclusion, Rab29 is an important regulator in the LRRK2-related pathway, potentially playing a role in Parkinson's disease. The gene knockout mouse models have provided insights into its function in LRRK2-mediated phosphorylation and locomotor behavior, although its exact role in disease-related pathology remains to be further explored.

References:

1. Zhu, Hanwen, Tonelli, Francesca, Turk, Martin, Alessi, Dario R, Sun, Ji. 2023. Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2. In Science (New York, N.Y.), 382, 1404-1411. doi:10.1126/science.adi9926. https://pubmed.ncbi.nlm.nih.gov/38127736/

2. Gomez, Rachel C, Vides, Edmundo G, Pfeffer, Suzanne R. . Rab29 Fast Exchange Mutants: Characterization of a Challenging Rab GTPase. In Methods in molecular biology (Clifton, N.J.), 2293, 19-25. doi:10.1007/978-1-0716-1346-7_2. https://pubmed.ncbi.nlm.nih.gov/34453707/

3. Kalogeropulou, Alexia F, Freemantle, Jordana B, Lis, Pawel, Polinski, Nicole K, Alessi, Dario R. . Endogenous Rab29 does not impact basal or stimulated LRRK2 pathway activity. In The Biochemical journal, 477, 4397-4423. doi:10.1042/BCJ20200458. https://pubmed.ncbi.nlm.nih.gov/33135724/

4. Purlyte, Elena, Dhekne, Herschel S, Sarhan, Adil R, Pfeffer, Suzanne R, Alessi, Dario R. 2017. Rab29 activation of the Parkinson's disease-associated LRRK2 kinase. In The EMBO journal, 37, 1-18. doi:10.15252/embj.201798099. https://pubmed.ncbi.nlm.nih.gov/29212815/

5. Mazza, Melissa Conti, Nguyen, Victoria, Beilina, Alexandra, Bishop, Christopher, Cookson, Mark R. . Combined Knockout of Lrrk2 and Rab29 Does Not Result in Behavioral Abnormalities in vivo. In Journal of Parkinson's disease, 11, 569-584. doi:10.3233/JPD-202172. https://pubmed.ncbi.nlm.nih.gov/33523017/