PDF(Pubmed)
Abstract：
Mutations in GBA1 cause Gaucher disease and are the most important genetic risk factor for Parkinson\'s disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, GBAP1. We show that >50% of short RNA-sequencing reads mapping to GBA1 also map to GBAP1. Thus, we used long-read RNA sequencing in the human brain, which allowed us to accurately quantify expression from both GBA1 and GBAP1. We discovered significant differences in expression compared to short-read data and identify currently unannotated transcripts of both GBA1 and GBAP1. These included protein-coding transcripts from both genes that were translated in human brain, but without the known lysosomal function-yet accounting for almost a third of transcription. Analyzing brain-specific cell types using long-read and single-nucleus RNA sequencing revealed region-specific variations in transcript expression. Overall, these findings suggest nonlysosomal roles for GBA1 and GBAP1 with implications for our understanding of the role of GBA1 in health and disease.
摘要：
GBA1突变可引起戈谢病，是帕金森病最重要的遗传危险因素。然而,该位点的转录分析因其高度同源的假基因而变得复杂，GBAP1。我们显示映射到GBA1的>50%的短RNA测序读取也映射到GBAP1。因此，我们在人脑中使用了长读RNA测序，这使我们能够准确地量化GBA1和GBAP1的表达。我们发现与短读数据相比表达的显着差异，并鉴定了GBA1和GBAP1的当前未注释转录本。这些包括来自两个基因的蛋白质编码转录本，这些转录本在人脑中翻译，但没有已知的溶酶体功能，但几乎占转录的三分之一。使用长读和单核RNA测序分析脑特异性细胞类型揭示了转录本表达的区域特异性变化。总的来说,这些发现提示了GBA1和GBAP1的非溶酶体作用,这对我们理解GBA1在健康和疾病中的作用有意义.
