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"Deciphering the role of αβ-crystallin in huntington’s disease"
Publication . Oliveira, Ana Cristina Osório Marinho; Outeiro, Tiago Fleming, 1976-; Finkbeiner, Steven Michael; Muchoswki, Paul Joseph
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 based on studies 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 or diminishing αBc levels in vivo modulates aggregation and the onset and progression of disease in a full-length mouse model of HD known as the 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. In Chapter 3, 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 act in a non-cell-autonomous manner. At the protein level, αBc decreased the levels of soluble mHtt and decreased the size of mHtt inclusions in BACHD brain. These results support a model in which elevating astrocytic αBc confers neuroprotection through a putative non-cell-autonomous pathway that modulates mHtt aggregation and protein levels. In Chapter 4, we attempted to elucidate the non-autonomous mechanism by which overexpressing astrocytic αBc confers neuroprotection in the progression of the disease of the BACHD mice. Several essential cellular pathways are impaired in neurological disorders such as HD. Among others, activation of caspase-3 pathways as well as formation of carbonyl species are oxidative stress hallmarks of HD pathology, and αBc has been reported to play a role in these mechanisms. Our studies, looking at mRNA and protein levels from BACHD mice as well as from primary cells (astrocytic and neuronal), found no significant differences in caspase-3 activation, and in expression of several HD markers, e.g., Glucose transporter 1 (Glut1), dopamine receptor 1 (DR1) and dopamine receptor 2 (DR2), brain-derived neurotrophic factor (BDNF), in this disease context. Despite not finding a significant difference, when looking at the formation of protein carbonyls (derived from oxidative stress), we found a small trend towards a decrease of the levels of these species when αBc was overexpressed in astrocytes, both in brains and primary cultures of BACHD. These data may support the potential antioxidant effect of αBc in the context of HD pathology. In Chapter 5, we hypothesized that αBc deficiency would accelerate HD disease severity and progression, as previously observed in a mouse model of Alzheimer’s Disease (AD). We tested this hypothesis by crossing mice null for αBc (and HspB2) to BACHD mice and monitoring behavioral and neuropathological symptoms of HD during disease progression. Our study showed that genetic deficiency of αBc (and HspB2) did not aggravate disease progression. Taken together, the results presented in this thesis provide novel insight into the role of αBc and its function on essential cellular pathways in the context of HD. This work also supports the emerging significance of non-neuronal cells in chronic diseases such as HD suggesting adaptive and differential responses that might contribute to and/or provide a route to therapy of distinct aspects of neurodegeneration. Ultimately, this knowledge aims to promote and highlight the impact and role of sHsps, specifically αBc, in HD and related disorders in order to help the development of promising therapeutics for these devastating diseases.
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Fundação para a Ciência e a Tecnologia
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SFRH
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SFRH/BD/65942/2009