Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy

• DOI: 10.1073/pnas.1300398110
• Publication Date: 2013-02-12T03:48:58Z
• Authors: Andrea Serio; Bilada Bilican; Sami J. Barmada; Dale Michael Ando; Chen Zhao; Rick Siller; Karen Burr; Ghazal Haghi; David Story; Agnes Lumi Nishimura; Monica A. Carrasco; Hemali P. Phatnani; Carole Shum; Ian Wilmut; Tom Maniatis; Christopher E. Shaw; Steven Finkbeiner; Siddharthan Chandran
• Keywords: Male; 570; glia; Cell Survival; Induced Pluripotent Stem Cells; 610; Neurodegenerative; Biochemistry; AMYOTROPHIC-LATERAL-SCLEROSIS; DISEASE; Cell Line; PATHWAY; Rare Diseases; Clinical Research; Stem Cell Research - Nonembryonic - Human; ASTROGLIOSIS; disease modeling; 2.1 Biological and endogenous factors; Humans; Aetiology; Cell Proliferation; Motor Neurons; FRONTOTEMPORAL LOBAR DEGENERATION; Biomedical and Clinical Sciences; Stem Cell Research - Induced Pluripotent Stem Cell; FOS: Clinical medicine; Amyotrophic Lateral Sclerosis; Neurosciences; PRECURSOR CELLS; Biological Sciences; Middle Aged; Stem Cell Research; Coculture Techniques; MUTANT SOD1; Brain Disorders; DNA-Binding Proteins; DIFFERENTIATION; Astrocytes; Neurological; Mutation; motor neuron disease; MOTOR-NEURONS; Biochemistry and Cell Biology; SPINAL-CORD; ALS

Glial proliferation and activation are associated with disease progression in amyotrophic lateral sclerosis (ALS) frontotemporal lobar dementia. In this study, we describe a unique platform to address the question of cell autonomy tran s active response DNA-binding protein (TDP-43) proteinopathies. We generated functional astroglia from human induced pluripotent stem cells carrying an ALS-causing TDP-43 mutation show that mutant astrocytes exhibit increased levels TDP-43, subcellular mislocalization decreased survival. then performed coculture experiments evaluate effects M337V on survival wild-type motor neurons, showing do not adversely affect cocultured neurons. These observations reveal significant previously unrecognized glial cell-autonomous pathological phenotype pathogenic proteinopathies display astrocyte non-cell-autonomous component culture, as described for SOD1 ALS. This study highlights utility cell-based vitro models investigate mechanisms ALS other