TY - JOUR
T1 - Alpha-Synuclein Induces the Unfolded Protein Response in Parkinson's Disease SNCA Triplication iPSC-Derived Neurons
AU - Heman-Ackah, Sabrina M
AU - Manzano, Raquel
AU - Hoozemans, Jeroen J M
AU - Scheper, Wiep
AU - Flynn, Rowan
AU - Haerty, Wilfried
AU - Cowley, Sally A
AU - Bassett, Andrew R
AU - Wood, Matthew J A
PY - 2017/1/1
Y1 - 2017/1/1
N2 - The recent generation of induced pluripotent stem cells (iPSCs) from a patient with Parkinson's disease (PD) resulting from triplication of the α-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 IRE1α/XBP1 axis of the unfolded protein response (UPR) and culminating in terminal UPR activation. Neuropathological analysis of post-mortem brain tissue demonstrated that pIRE1α is expressed in PD brains within neurons containing elevated levels of α-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.
AB - The recent generation of induced pluripotent stem cells (iPSCs) from a patient with Parkinson's disease (PD) resulting from triplication of the α-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 IRE1α/XBP1 axis of the unfolded protein response (UPR) and culminating in terminal UPR activation. Neuropathological analysis of post-mortem brain tissue demonstrated that pIRE1α is expressed in PD brains within neurons containing elevated levels of α-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.
KW - Journal Article
UR - http://www.scopus.com/inward/record.url?scp=85034253461&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85034253461&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/hmg/ddx331
DO - https://doi.org/10.1093/hmg/ddx331
M3 - Article
C2 - 28973645
SN - 0964-6906
VL - 26
SP - 4441
EP - 4450
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 22
ER -
