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The sHsp expression signature in the brain and modulation in models of chronic neurodegeneration

Record type: Thesis (Doctoral)

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 ?-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 (?Bcrystallin).
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.

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Citation

Quraishe, Shmma (2010) The sHsp expression signature in the brain and modulation in models of chronic neurodegeneration University of Southampton Doctoral Thesis , 305pp.

More information

Published date: 2 April 2010
Organisations: University of Southampton

Identifiers

Local EPrints ID: 160233
URI: http://eprints.soton.ac.uk/id/eprint/160233
PURE UUID: 3be9d256-915e-43d9-9a07-0f85bfa0503c

Catalogue record

Date deposited: 15 Jul 2010 15:35
Last modified: 18 Jul 2017 12:35

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Contributors

Author: Shmma Quraishe
Thesis advisor: Vincent O'connor
Thesis advisor: ANDREAS WYTTENBACH

University divisions


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