title: HDAC6 Inhibitors Rescued the Defective Axonal Mitochondrial Movement in Motor Neurons Derived from the Induced Pluripotent Stem Cells of Peripheral Neuropathy Patients withHSPB1Mutation.
abstract: The Charcot-Marie-Tooth disease 2F (CMT2F) and distal hereditary motor neuropathy 2B (dHMN2B) are caused by autosomal dominantly inherited mutations of the heat shock 27 kDa protein 1 (HSPB1) gene and there are no specific therapies available yet. Here, we assessed the potential therapeutic effect of HDAC6 inhibitors on peripheral neuropathy withHSPB1mutation using in vitro model of motor neurons derived from induced pluripotent stem cells (iPSCs) of CMT2F and dHMN2B patients. The absolute velocity of mitochondrial movements and the percentage of moving mitochondria in axons were lower both in CMT2F-motor neurons and in dHMN2B-motor neurons than those in controls, and the severity of the defective mitochondrial movement was different between the two disease models. CMT2F-motor neurons and dHMN2B-motor neurons also showed reducedα-tubulin acetylation compared with controls. The newly developed HDAC6 inhibitors, CHEMICAL X4 and CHEMICAL X9, increased acetylation ofα-tubulin and reversed axonal movement defects of mitochondria in CMT2F-motor neurons and dHMN2B-motor neurons. Our results suggest that the neurons derived from patient-specific iPSCs can be used in drug screening including HDAC6 inhibitors targeting peripheral neuropathy.
authors.affiliation: Department of Microbiology, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Ji-Yon
authors.identifier: 0000-0002-2983-096X
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Microbiology, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: So-Youn
authors.identifier: 0000-0001-6902-0315
authors.initials: SY
authors.lastname: Woo
authors.affiliation: Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Young Bin
authors.initials: YB
authors.lastname: Hong
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Heesun
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jisoo
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Republic of Korea.
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
authors.affiliation: Chong Kun Dang Research Institute, Yongin-si, Gyeonggi-do, Republic of Korea.
authors.forename: Nina
authors.initials: N
authors.lastname: Ha
authors.affiliation: Chong Kun Dang Research Institute, Yongin-si, Gyeonggi-do, Republic of Korea.
authors.forename: Jangbeen
authors.initials: J
authors.lastname: Kyung
authors.affiliation: Division of Intractable Diseases, Center for Biomedical Sciences, National Institute of Health, Chungcheongbuk-do, Republic of Korea.
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Koo
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Sung-Chul
authors.identifier: 0000-0002-3174-8965
authors.initials: SC
authors.lastname: Jung
authors.affiliation: Departments of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Byung-Ok
authors.identifier: 0000-0001-5459-1772
authors.initials: BO
authors.lastname: Choi