Quantitative proteomic analysis of induced pluripotent stem cells derived from a human Huntington's disease patient.
HD (Huntington's disease) is a devastating neurodegenerative genetic disorder caused by abnormal expansion of CAG repeats in the HTT (huntingtin) gene. We have recently established two iPSC (induced pluripotent stem cell) lines derived from a HD patient carrying 72 CAG repeats (HD-iPSC). In order to understand the proteomic profiles of HD-iPSCs, we have performed comparative proteomic analysis among normal hESCs (human embryonic stem cells; H9), iPSCs (551-8) and HD-iPSCs at undifferentiated stages, and identified 26 up- and down-regulated proteins. Interestingly, these differentially expressed proteins are known to be involved in different biological processes, such as oxidative stress, programmed cell death and cellular oxygen-associated proteins. Among them, we found that oxidative stress-related proteins, such as SOD1 (superoxide dismutase 1) and Prx (peroxiredoxin) families are particularly affected in HD-iPSCs, implying that HD-iPSCs are highly susceptible to oxidative stress. We also found that BTF3 (basic transcription factor 3) is up-regulated in HD-iPSCs, which leads to the induction of ATM (ataxia telangiectasia mutated), followed by activation of the p53-mediated apoptotic pathway. In addition, we observed that the expression of cytoskeleton-associated proteins was significantly reduced in HD-iPSCs, implying that neuronal differentiation was also affected. Taken together, these results demonstrate that HD-iPSCs can provide a unique cellular disease model system to understand the pathogenesis and neurodegeneration mechanisms in HD, and the identified proteins from the present study may serve as potential targets for developing future HD therapeutics.
Department of Oral Pharmacology, School of Dentistry and Institute of Dental Bioscience, BK21 project, Chonbuk National University, Jeonju 651-756, Korea.
Jung-Il
JI
Chae
Dong-Wook
DW
Kim
Nayeon
N
Lee
Young-Joo
YJ
Jeon
Iksoo
I
Jeon
Jihye
J
Kwon
Jumi
J
Kim
Yunjo
Y
Soh
Dong-Seok
DS
Lee
Kang Seok
KS
Seo
Nag-Jin
NJ
Choi
Byoung Chul
BC
Park
Sung Hyun
SH
Kang
Joohyun
J
Ryu
Seung-Hun
SH
Oh
Dong Ah
DA
Shin
Dong Ryul
DR
Lee
Jeong Tae
JT
Do
In-Hyun
IH
Park
George Q
GQ
Daley
Jihwan
J
Song
D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D040901:Proteomics; D019680:Trinucleotide Repeat Expansion
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins