Chromosomal instability during neurogenesis in Huntington's disease

Chromosomal instability during neurogenesis in Huntington's disease

Huntington's disease (HD) is a fatal neurodegenerative disease caused by expansion of CAG repeats in the Huntingtin gene ( ). Neither its pathogenic mechanisms nor the normal functions of HTT are well understood. To model HD in humans, we engineered a genetic allelic series of isogenic human em...

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Bibliographic Details
Published in:Development (Cambridge) Vol. 145; no. 2; p. dev156844
Main Authors: Ruzo, Albert, Croft, Gist F, Metzger, Jakob J, Galgoczi, Szilvia, Gerber, Lauren J, Pellegrini, Cecilia, Wang, Jr, Hanbin, Fenner, Maria, Tse, Stephanie, Marks, Adam, Nchako, Corbyn, Brivanlou, Ali H
Format: Journal Article
Language:English
Published: England The Company of Biologists Ltd 15-01-2018
Subjects:
Cytokinesis
Developmental disabilities
DNA biosynthesis
Genomic instability
Huntingtin
Huntington's disease
Huntingtons disease
Neurogenesis
Phenotypes
Polyglutamine
Stem cells
Telencephalon
Trinucleotide repeat diseases
Trinucleotide repeats
Human embryonic stem cells
CRISPR
DNA damage and repair
Disease modeling
Chromosomal instability
Huntington's disease
Neurogenesis
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Summary:Huntington's disease (HD) is a fatal neurodegenerative disease caused by expansion of CAG repeats in the Huntingtin gene ( ). Neither its pathogenic mechanisms nor the normal functions of HTT are well understood. To model HD in humans, we engineered a genetic allelic series of isogenic human embryonic stem cell (hESC) lines with graded increases in CAG repeat length. Neural differentiation of these lines unveiled a novel developmental HD phenotype: the appearance of giant multinucleated telencephalic neurons at an abundance directly proportional to CAG repeat length, generated by a chromosomal instability and failed cytokinesis over multiple rounds of DNA replication. We conclude that disrupted neurogenesis during development is an important, unrecognized aspect of HD pathogenesis. To address the function of normal HTT protein we generated and lines. Surprisingly, the same phenotype emerged in but not lines. We conclude that HD is a developmental disorder characterized by chromosomal instability that impairs neurogenesis, and that HD represents a genetic dominant-negative loss of function, contrary to the prevalent gain-of-toxic-function hypothesis. The consequences of developmental alterations should be considered as a new target for HD therapies.
ISSN:0950-1991
1477-9129
DOI:10.1242/dev.156844