title: Proteasome impairment in neural cells derived from HMSN-P patient iPSCs.
abstract: Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is caused by a heterozygous mutation (P285L) in Tropomyosin-receptor kinase Fused Gene (TFG), histopathologically characterized by progressive spinal motor neuron loss with TFG cytosolic aggregates. Although the TFG protein, found as a type of fusion oncoprotein, is known to facilitate vesicle transport from endoplasmic reticulum (ER) to Golgi apparatus at ER exit site, it is unclear how mutant TFG causes motor neuron degeneration. Here we generated induced pluripotent stem cells (iPSCs) from HMSN-P patients, and differentiated the iPSCs into neural cells with spinal motor neurons (iPS-MNs). We found that HMSN-P patient iPS-MNs exhibited ubiquitin proteasome system (UPS) impairment, and HMSN-P patient iPS-MNs were vulnerable to UPS inhibitory stress. Gene correction of the mutation in TFG using the CRISPR-Cas9 system reverted the cellular phenotypes of HMSN-P patient iPS-MNs. Collectively, these results suggest that our cellular model with defects in cellular integrity including UPS impairments may lead to identification of pathomechanisms and a therapeutic target for HMSN-P.
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.|Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan.
authors.forename: Nagahisa
authors.initials: N
authors.lastname: Murakami
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Imamura
authors.affiliation: Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan.
authors.forename: Yuishin
authors.initials: Y
authors.lastname: Izumi
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Egawa
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Tsukita
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Enami
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kawarai
authors.affiliation: Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kaji
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan. haruhisa@cira.kyoto-u.ac.jp.
authors.forename: Haruhisa
authors.identifier: 0000-0001-8270-4025
authors.initials: H
authors.lastname: Inoue
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation; D002999:Clone Cells; D005260:Female; D015417:Hereditary Sensory and Motor Neuropathy / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011506:Proteins / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology; D033921:Vesicular Transport Proteins
chemical_list: D046988:Proteasome Endopeptidase Complex; D011506:Proteins; C096163:TFG protein, human; D033921:Vesicular Transport Proteins
keywords: CRISPR-Cas9; Gene correction; HMSN-P; Neurodegeneration; TFG; UPS; iPSCs