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

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

Hum Mol Genet

Gladstone Institute for Neurological Disease, J. David Gladstone Institutes, San Francisco, CA, USA, Department of Neurology, Department of Physiology, University of California at San Francisco, San Francisco, CA, USA and Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA, USA

Published: May 2016

AI Article Synopsis

Article 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. αB-crystallin (αBc) 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 αBc 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, αBc is mainly found in astrocytes and oligodendrocytes. Here, we show that directed αBc 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 αBc overexpression was neuroprotective against neuronal cell loss in BACHD brains, suggesting αBc might be acting in a non-cell-autonomous manner. At the protein level, αBc 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 αBc confers neuroprotection through a potential non-cell-autonomous pathway that modulates mhtt aggregation and protein levels.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986324PMC
http://dx.doi.org/10.1093/hmg/ddw028DOI Listing

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