title: Stem cell-derived motor neurons from spinal and bulbar muscular atrophy patients.
abstract: Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is a motor neuron disease caused by polyglutamine repeat expansion in the androgen receptor. Although degeneration occurs in the spinal cord and muscle, the exact mechanism is not clear. Induced pluripotent stem cells from spinal and bulbar muscular atrophy patients provide a useful model for understanding the disease mechanism and designing effective therapy. Stem cells were generated from six patients and compared to control lines from three healthy individuals. Motor neurons from four patients were differentiated from stem cells and characterized to understand disease-relevant phenotypes. Stem cells created from patient fibroblasts express less androgen receptor than control cells, but show androgen-dependent stabilization and nuclear translocation. The expanded repeat in several stem cell clones was unstable, with either expansion or contraction. Patient stem cell clones produced a similar number of motor neurons compared to controls, with or without androgen treatment. The stem cell-derived motor neurons had immunoreactivity for HB9, Isl1, ChAT, and SMI-32, and those with the largest repeat expansions were found to have increased acetylated α-tubulin and reduced HDAC6. Reduced HDAC6 was also found in motor neuron cultures from two other patients with shorter repeats. Evaluation of stably transfected mouse cells and SBMA spinal cord showed similar changes in acetylated α-tubulin and HDAC6. Perinuclear lysosomal enrichment, an HDAC6 dependent process, was disrupted in motor neurons from two patients with the longest repeats. SBMA stem cells present new insights into the disease, and the observations of reduced androgen receptor levels, repeat instability, and reduced HDAC6 provide avenues for further investigation of the disease mechanism and development of effective therapy.
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 2A-1000 Building 35, 35 Convent Drive, NIH, Bethesda, MD 20892, USA. Electronic address: christopher.grunseich@nih.gov.
authors.forename: Christopher
authors.initials: C
authors.lastname: Grunseich
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 2A-1000 Building 35, 35 Convent Drive, NIH, Bethesda, MD 20892, USA. Electronic address: kristen.perkins@nih.gov.
authors.forename: Kristen
authors.initials: K
authors.lastname: Zukosky
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 2A-1000 Building 35, 35 Convent Drive, NIH, Bethesda, MD 20892, USA. Electronic address: Ilona.kats@nih.gov.
authors.forename: Ilona R
authors.initials: IR
authors.lastname: Kats
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 2A-1000 Building 35, 35 Convent Drive, NIH, Bethesda, MD 20892, USA. Electronic address: labonighosh@gmail.com.
authors.forename: Laboni
authors.initials: L
authors.lastname: Ghosh
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 2A-1000 Building 35, 35 Convent Drive, NIH, Bethesda, MD 20892, USA. Electronic address: george.harmison@nih.gov.
authors.forename: George G
authors.initials: GG
authors.lastname: Harmison
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 2A-1000 Building 35, 35 Convent Drive, NIH, Bethesda, MD 20892, USA; Department of Cell and Molecular Biology, Karolinska Institute, Solnavagen 1, 17177 Solna, Sweden. Electronic address: laura.bott@nih.gov.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Bott
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 2A-1000 Building 35, 35 Convent Drive, NIH, Bethesda, MD 20892, USA. Electronic address: carlo.rinaldi@nih.gov.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rinaldi
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 2A-1000 Building 35, 35 Convent Drive, NIH, Bethesda, MD 20892, USA. Electronic address: chenk@ninds.nih.gov.
authors.forename: Ke-lian
authors.initials: KL
authors.lastname: Chen
authors.affiliation: National Heart, Lung and Blood Institute, Bld 10-CRC Rm 5-3132, 10 Center Dr., NIH, Bethesda, MD 20892, USA. Electronic address: guibin.chen@nih.gov.
authors.forename: Guibin
authors.initials: G
authors.lastname: Chen
authors.affiliation: National Heart, Lung and Blood Institute, Bld 10-CRC Rm 5-3132, 10 Center Dr., NIH, Bethesda, MD 20892, USA. Electronic address: manfred.boehm@nih.gov.
authors.forename: Manfred
authors.initials: M
authors.lastname: Boehm
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 2A-1000 Building 35, 35 Convent Drive, NIH, Bethesda, MD 20892, USA. Electronic address: kf@ninds.nih.gov.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
mesh_terms: D000107:Acetylation; D000328:Adult; D000368:Aged; D055534:Bulbo-Spinal Atrophy, X-Linked / Q000235:genetics / Q000503:physiopathology*; D002478:Cells, Cultured; D042622:DNA Repeat Expansion; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000172:deficiency; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology; D011944:Receptors, Androgen / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D055815:Young Adult
chemical_list: D011944:Receptors, Androgen; D014404:Tubulin; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: Androgen receptor; Induced pluripotent stem cells; Motor neuron disease; Spinal and bulbar muscular atrophy