αB-Crystallin overexpression in astrocytes modulates the phenotype of the BACHD mouse model of Huntington's disease
| Autor: | Ana Osório Oliveira, Paul J. Muchowski, Steven Finkbeiner, Alexander P. Osmand, Tiago F. Outeiro |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Huntington's Disease Huntingtin Neurodegenerative Medical and Health Sciences Transgenic Mice 0302 clinical medicine 2.1 Biological and endogenous factors Aetiology Genetics (clinical) Neurons Genetics & Heredity Huntingtin Protein Behavior Animal Brain General Medicine Articles Biological Sciences Phenotype Cell biology Huntington Disease Neurological Transgene Mice Transgenic Biology Neuroprotection 03 medical and health sciences Rare Diseases Huntington's disease Crystallin Heat shock protein Genetics medicine Animals Humans Molecular Biology Behavior Animal Neurosciences alpha-Crystallin B Chain medicine.disease Molecular biology Brain Disorders Disease Models Animal 030104 developmental biology Astrocytes Disease Models 030217 neurology & neurosurgery |
| Zdroj: | Human molecular genetics, vol 25, iss 9 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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