Stem cell-derived motor neurons from spinal and bulbar muscular atrophy patients

Christopher Grunseich*, Kristen Zukosky, Ilona R. Kats, Laboni Ghosh, George G. Harmison, Laura C. Bott, Carlo Rinaldi, Ke lian Chen, Guibin Chen, Manfred Boehm, Kenneth H. Fischbeck

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)12-20
Number of pages9
JournalNeurobiology of Disease
Volume70
DOIs
StatePublished - Oct 2014

Funding

This work was supported by intramural funding from the National Center for Regenerative Medicine and the National Institute of Neurological Disorders and Stroke , NIH.

Keywords

  • Androgen receptor
  • Induced pluripotent stem cells
  • Motor neuron disease
  • Spinal and bulbar muscular atrophy

ASJC Scopus subject areas

  • Neurology

Fingerprint

Dive into the research topics of 'Stem cell-derived motor neurons from spinal and bulbar muscular atrophy patients'. Together they form a unique fingerprint.

Cite this