Journal
HUMAN MOLECULAR GENETICS
Volume 25, Issue 9, Pages 1677-1689Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddw028
Keywords
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Funding
- Fundacao para Ciencia e Tecnologia [SFRH/BD/65942/2009]
- National Institutes of Neurological Disorders and Stroke [3R01 NS039074, 2R01 NS045091]
- Taube/Koret Center for Neurodegenerative Disease
- Hellman Family Foundation Alzheimer's Disease Research Program
- DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain
- National Center for Research Resources [RR18928]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/65942/2009] Funding Source: FCT
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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. alpha B-crystallin (alpha Bc) or HspB5 is awell-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 alpha Bc in vivo modulates aggregation and delays the onset and progression of disease in a full-length model of HD, BACHDmice. Expression of sHsps in neurodegenerative disease predominantly occurs in non-neuronal cells, and in the brain, alpha Bc is mainly found in astrocytes and oligodendrocytes. Here, we show that directed alpha 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 alpha Bc overexpressionwas neuroprotective against neuronal cell loss in BACHD brains, suggesting alpha Bc might be acting in a non-cell-autonomous manner. At the protein level, alpha 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 alpha Bc confers neuroprotection through a potential non-cell-autonomous pathway that modulates mhtt aggregation and protein levels.
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