Nature Structural & Molecular Biology, Год журнала: 2024, Номер 31(12), С. 1955 - 1963

Опубликована: Дек. 1, 2024

Abstract Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase ( GBA1 ). This variant rs3115534 -G) is carried by ~50% of West PD cases and imparts a dose-dependent increase in for disease. The has varied frequencies across ancestry groups but almost absent European Asian populations. high clinical therapeutic interest. Damaging biallelic protein-coding variants cause Gaucher monoallelic confer dementia with Lewy bodies, likely reducing function glucocerebrosidase. Interestingly, noncoding variant, suggesting different mechanism action. Using full-length RNA transcript sequencing, we partial intron 8 expression carriers (G) not nonvariant (T). Antibodies targeting N terminus showed that this intron-retained isoform protein coding subsequent proteomics did identify shorter isoform, based. Clustered regularly interspaced short palindromic repeats editing reported index ) revealed sequence alteration responsible driving production these transcripts containing 8. Follow-up analysis it key intronic branchpoint and, therefore, important implications splicing In addition, when measuring activity, reduction carriers. Overall, report functional effect which acts interfering transcripts, resulting reduced levels activity. understanding reveals potential target underserved underrepresented population.

Язык: Английский