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

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

Name dc:type.qualificationname

Ph.D.

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of Southampton

Year dc:date.issued

2010

Author dc:creator

• Quraishe, Shmma

Advisors dc:contributor.advisor

• O'Connor, Vincent
• Wyttenbach, Andreas