Prpf19 a potential new target in hereditary ataxia model

Researchers from the Chinese University of Hong Kong (CUHK) have unveiled the involvement of an E3 ligase pre-mRNA processing factor 19 (Prpf19) in spinocerebellar ataxia type 3 (SCA3) pathogenesis and found its interacting partner, exocyst complex component 7 (Exoc7), to have an opposite modulating effect on disease protein ataxin-3 (ATXN3).

SCA3, also known as Machado-Joseph Disease, is the most common form of dominantly inherited ataxia in many populations worldwide. [Neurobiol Dis 2020;134:104635] SCA3 is a polyglutamine (polyQ) neurodegenerative disorder caused by the expansion of glutamine coding CAG repeats in ATXN3, leading to the formation of insoluble protein aggregates, which hinders neuronal survival and results in neurodegeneration. [Brain Pathol 2017;27:345-355] To date, SCA3 remains an incurable disorder.

Earlier studies have indicated that Prpf19 E3 function plays a role in the maturation of the mouse brain, but the current study is the first to show its involvement in human neurological disease. [J Biol Chem 2006:281:7498-7514] “We showed that Prpf19 protein interacts with mutant ATXN3-polyQ protein and targets it for ubiquitination and degradation. Using in vitro mammalian cell and in vivo Drosophila models, we found that overexpression of Prpf19/prp19 reduces the level of expanded ATXN3-polyQ protein, as well as ameliorates SCA3 cytotoxicities and neurodegeneration, while knockdown of Prpf19/prp19 exerts an opposite effect,” wrote the researchers. [Cell Death & Disease 2021;12:136]

“Most interestingly, we observed that this modulatory effect is mediated via nuclear but not cytoplasmic Prpf19,” they continued. The researchers were able to ascertain the requirement for nuclear localization of Prpf19 for successful ubiquitination and degradation of ATXN3-polyQ protein by generating a cytosolic version of Prpf19, which failed to modify ATXN3-polyQ protein levels, meaning it could aggregate and become toxic.

Based on reports of physical interaction of Prpf19 with Exoc7, the researchers investigated whether the co-expression of Exoc7 would modify Prpf19’s modulatory effect on ATXN3-polyQ protein toxicity. [Small GTPases 2019;10:331-335]

“We found that the co-expression of full-length Exoc7 counteracted Prpf19’s ability in reducing ATXN3-polyQ protein level, as well as suppressing ATXN3-polyQ–induced caspase-3 cleavage. At the same time, Prpf19 overexpression promoted poly-ubiquitination of expanded ATXN3-polyQ protein, and such effect was abolished upon Exoc7 co-expression” they reported.

“The current study demonstrates an intricate relationship between Prpf19 and Exoc7, two crucial proteins in nerve cells. Elucidating the mechanism of action of protein networks that govern protein aggregation will allow us to develop potential small molecules or activators targeting Prpf19, with the hope of providing novel strategies for curing SCA3 and other neurodegenerative disorders,” concluded Professor Edwin Chan of CUHK’s School of Life Sciences. “SCA3 belongs to the category of rare neurodegenerative diseases and I hope that our findings will provide an insight into rare disease translational biomedicine research.”