Alpha-synuclein induces the unfolded protein response in Parkinson%26apos;s disease SNCA triplication iPSC-derived neurons

作者：Heman Ackah Sabrina M; Manzano Raquel; Hoozemans Jeroen J M; Scheper Wiep; Flynn Rowan; Haerty Wilfried; Cowley Sally A; Bassett Andrew R; Wood Matthew J A

来源：Human Molecular Genetics, 2017, 26(22): 4441-4450.

DOI：10.1093/hmg/ddx331

The recent generation of induced pluripotent stem cells (iPSCs) from a patient with Parkinson's disease (PD) resulting from triplication of the alpha-synuclein (SNCA) gene locus allows unprecedented opportunities to explore its contribution to the molecular pathogenesis of PD. We used the double-nicking CRISPR/Cas9 system to conduct site-specific mutagenesis of SNCA in these cells, generating an isogenic iPSC line with normalized SNCA gene dosage. Comparative gene expression analysis of neuronal derivatives from these iPSCs revealed an ER stress phenotype, marked by induction of the IRE1 alpha/XBP1 axis of the unfolded protein response (UPR) and culminating in terminal UPR activation. Neuropathological analysis of post-mortem brain tissue demonstrated that pIRE1 alpha is expressed in PD brains within neurons containing elevated levels of alpha-synuclein or Lewy bodies. Having used this pair of isogenic iPSCs to define this phenotype, these cells can be further applied in UPR-targeted drug discovery towards the development of disease-modifying therapeutics.

• 出版日期2017-11-15
• 单位NIH