Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease

NEUROBIOLOGY OF DISEASE

卷:96

Article

Arteaga-Bracho, Eduardo E.^1,2,4,6  Gulinello, Maria^4,6,11  Winchester, Michael L.^1,2,3,6  Pichamoorthy, Nandini^1,2,3,6  Petronglo, Jenna R.^1,2,3,6  Zambrano, Alicia D.^1,2,3  Inocencio, Julio³  De Jesus, Chirstopher D.^1,2,4,6  Louie, Joseph O.³  Gokhan, Solen^1,2,3,6  Mehler, Mark F.^{1,2,3,4,5,6,7,8,9,10}  Molero, Aldrin E.^1,2,3,6 

[1] Albert Einstein Coll Med, Roslyn & Leslie Goldstein Lab Stem Cell Biol & Re, Bronx, NY 10467 USA

[2] Albert Einstein Coll Med, Inst Brain Disorders & Neural Regenerat, Bronx, NY 10467 USA

[3] Albert Einstein Coll Med, Saul R Korey Dept Neurol, Bronx, NY 10467 USA

[4] Albert Einstein Coll Med, Dominick P Purpura Dept Neurosci, Bronx, NY 10467 USA

[5] Albert Einstein Coll Med, Dept Psychiat & Behav Sci, Bronx, NY 10467 USA

[6] Albert Einstein Coll Med, Rose F Kennedy Ctr Res Intellectual & Dev Disabil, Bronx, NY 10467 USA

[7] Albert Einstein Coll Med, Einstein Canc Ctr, Bronx, NY 10467 USA

[8] Albert Einstein Coll Med, Ruth L & David S Gottesman Inst Stem Cell Biol &, Bronx, NY 10467 USA

[9] Albert Einstein Coll Med, Ctr Epigen, Bronx, NY 10467 USA

[10] Albert Einstein Coll Med, Inst Aging Res, Bronx, NY 10467 USA

[11] Albert Einstein Coll Med, Behav Core Facil, Bronx, NY 10467 USA

关键词: Huntingtin;    Development;    Degeneration;    Pathogenesis;    Neurogenesis;    Gliogenesis;    Myelin;    Loss-of-function;    Maturation;    Huntington's disease;   

DOI  :  10.1016/j.nbd.2016.09.006

来源: Elsevier

【 摘 要 】

The mutation in huntingtin (mHtt) leads to a spectrum of impairments in the developing forebrain of Huntington's disease (HD) mouse models. Whether these developmental alterations are due to loss- or gain-of-function mechanisms and contribute to HD pathogenesis is unknown. We examined the role of selective loss of huntingtin (Htt) function during development on postnatal vulnerability to cell death. We employed mice expressing very low levels of Htt throughout embryonic life to postnatal day 21 (Hdh(d.hyp)). We demonstrated that Hdh(d.hyp) mice exhibit: (1) late-life striatal and cortical neuronal degeneration; (2) neurological and skeletal muscle alterations; and (3) white matter tract impairments and axonal degeneration. Hdh(d.hyp) embryos also exhibited subpallial heterotopias, aberrant striatal maturation and deregulation of gliogenesis. These results indicate that developmental deficits associated with Htt functions render cells present at discrete neural foci increasingly susceptible to cell death, thus implying the potential existence of a loss-of-function developmental component to HD pathogenesis. (C) 2016 Elsevier Inc. All rights reserved.

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