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Title: The sHsp expression signature in the brain and modulation in models of chronic neurodegeneration
Author: Quraishe, Shmma
ISNI:       0000 0004 2690 1181
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2010
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Intrinsic protein folding pathways are modulated by molecular chaperones, such as the diverse group of heat shock proteins (Hsps). Among these is the small heat shock protein (sHsp) family which in the mammalian genome consists of 10 low molecular weight (15-30kDa) members. The sHsps have classical chaperone functions but additionally contribute to pathways that protect against cellular stresses, maintain the cytoskeleton, prevent protein aggregation and regulate apoptosis. They contain a characteristic C-terminal α-crystallin domain, which is exclusive to the sHsp family. In addition to their constitutive expression under physiological (non-disease) conditions, they are also induced under conditions of stress/heat shock which is thought to play a role in response to protein misfolding that underpins disease. There are a wide range of diseases in which the sHsps function or are dysfunctional by mutations, such as neurodegenerative disorders, cataract, and desmin related myopathy. Each of the 10 sHsps is believed to have a unique expression profile. Seven of the sHsps are expressed in heart and muscle, but little is known about their precise expression and/or physiological role in the CNS. In the present study the expression of the mammalian sHsps in various mouse tissues including the brain was investigated. This provided evidence for the constitutive expression of 4 sHsps in the brain. In situ hybridization using naïve adult mice revealed a distinct white matter (oligodendrocyte) specific expression pattern for HspB5 (αBcrystallin). HspB1 (Hsp25) and HspB8 (Hsp22) demonstrated overlapping expression in the lateral and dorsal ventricles of the brain, as well as expression in a distinct set of motor neurons in the ventral horn of the spinal cord. Further, cellular immunostaining and subfractionation of brain tissue supports a distinct cellular and subcellular protein expression of HspB1, HspB5, HspB6 (Hsp20) and HspB8 in the brain. Both HspB5 and HspB6 were enriched in the myelin fraction. In view of the potential for induction of these sHsps by stress and modulation in chronic brain diseases we systematically investigated the sHsp signature in two distinct models of intracellular (R6/2) and extracellular (ME7) proteinopathies. These models recapitulate key features of Huntington’s and prion disease, respectively. Analysis of the sHsps in the R6/2 Huntington’s disease (HD) mouse model showed a specific down-regulation of HspB5 in the white matter at all time points analyzed. All other sHsps investigated did not change in this model of HD. Analysis of the sHsps in ME7 prion disease showed up-regulation of HspB1, HspB5 and HspB8 in the hippocampus. For HspB1, this was selective to an anatomically defined sub-population of astrocytes distributed in the stratum radiatum. In contrast, all GFAP positive astrocytes throughout the hippocampus exhibited induced expression of HspB5 and HspB8. Based on QT-PCR data, the changes in expression of the sHsps in either model was not under transcriptional control, suggesting translation/posttranslational regulation. The differing results in the two models suggest that the presence of intracellular (R6/2) or extracellular (ME7) aggregates may dictate the sHsp response associated with non-neuronal cells. In view of the emerging significance of non-neuronal cells in chronic diseases the data supports adaptive and differential responses that might contribute to and/or provide a route to therapy of distinct aspects of neurodegeneration.
Supervisor: O'connor, Vincent ; Wyttenbach, Andreas Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RB Pathology ; RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry