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?B-Crystallin overexpression in astrocytes modulates the phenotype of the BACHD mouse model of Huntington's disease.


ABSTRACT: Huntington's disease (HD) is caused by an expanded polyglutamine (polyQ) tract in the huntingtin (htt) protein. The polyQ expansion increases the propensity of htt to aggregate and accumulate, and manipulations that mitigate protein misfolding or facilitate the clearance of misfolded proteins are predicted to slow disease progression in HD models. ?B-crystallin (?Bc) or HspB5 is a well-characterized member of the small heat shock protein (sHsp) family that reduces mutant htt (mhtt) aggregation and toxicity in vitro and in Drosophila models of HD. Here, we determined if overexpressing ?Bc in vivo modulates aggregation and delays the onset and progression of disease in a full-length model of HD, BACHD mice. Expression of sHsps in neurodegenerative disease predominantly occurs in non-neuronal cells, and in the brain, ?Bc is mainly found in astrocytes and oligodendrocytes. Here, we show that directed ?Bc overexpression in astrocytes improves motor performance in rotarod and balance beam tests and improves cognitive function in the BACHD mice. Improvement in behavioral deficits correlated with mitigation of neuropathological features commonly observed in HD. Interestingly, astrocytic ?Bc overexpression was neuroprotective against neuronal cell loss in BACHD brains, suggesting ?Bc might be acting in a non-cell-autonomous manner. At the protein level, ?Bc decreased the level of soluble mhtt and decreased the size of mhtt inclusions in BACHD brain. Our results support a model in which elevating astrocytic ?Bc confers neuroprotection through a potential non-cell-autonomous pathway that modulates mhtt aggregation and protein levels.

SUBMITTER: Oliveira AO 

PROVIDER: S-EPMC4986324 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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αB-Crystallin overexpression in astrocytes modulates the phenotype of the BACHD mouse model of Huntington's disease.

Oliveira Ana Osório AO   Osmand Alexander A   Outeiro Tiago Fleming TF   Muchowski Paul Joseph PJ   Finkbeiner Steven S  

Human molecular genetics 20160226 9


Huntington's disease (HD) is caused by an expanded polyglutamine (polyQ) tract in the huntingtin (htt) protein. The polyQ expansion increases the propensity of htt to aggregate and accumulate, and manipulations that mitigate protein misfolding or facilitate the clearance of misfolded proteins are predicted to slow disease progression in HD models. αB-crystallin (αBc) or HspB5 is a well-characterized member of the small heat shock protein (sHsp) family that reduces mutant htt (mhtt) aggregation a  ...[more]

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