title: Differential regulation of small heat shock proteins in transgenic mouse models of neurodegenerative diseases.
abstract: Previously, several studies have demonstrated changes in the levels of small heat shock proteins (sHSP) in the transgenic mouse models of familial amyotrophic lateral sclerosis (fALS) linked to mutations in Cu/Zn superoxide dismutase. Here, we compared the expression of sHSPs in transgenic mouse models of fALS, Parkinson's disease (PD), dentato-rubral pallido-luysian atrophy (DRPLA) and Huntington's disease (HD); where the expression of mutant cDNA genes was under the transcriptional regulation of the mouse prion protein promoter. These models express G37R mutant Cu/Zn superoxide dismutase (SOD1G37R; fALS), A53T mutant alpha-synuclein (alpha-SynA53T; PD), full-length mutant atrophin-1-65Q, and htt-N171-82Q (huntingtin N-terminal fragment; HD). We found that the levels and solubilities of two sHSPs, Hsp25 and alpha B-crystallin, were differentially regulated in these mice. Levels of both Hsp25 and alpha B-crystallin were markedly increased in subgroups of glias at the affected regions of symptomatic SODG37R and alpha-SynA53T transgenic mice; abnormal deposits or cells intensely positive for alpha B-crystallin were observed in SODG37R mice. By contrast, neither sHSP was induced in spinal cords of htt-N171-82Q or atrophin-1-65Q mice, which do not develop astrocytosis or major motor neuron abnormalities. Interestingly, the levels of insoluble alpha B-crystallin in spinal cords gradually increased as a function of age in nontransgenic animals. In vitro, alpha B-crystallin was capable of suppressing the aggregation of alpha-SynA53T, as previously described for a truncated mutant SOD1. The transgenes in these mice are expressed highly in astrocytes and thus our results suggest a role for small heat shock proteins in protecting activated glial cells such as astrocytes in neurodegenerative diseases.
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Room 558, Baltimore, MD 21205, USA. jiou.wang@yale.edu
authors.forename: Jiou
authors.initials: J
authors.lastname: Wang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Martin
authors.forename: Victoria
authors.initials: V
authors.lastname: Gonzales
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
authors.forename: Michael K
authors.initials: MK
authors.lastname: Lee
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D050888:Heat-Shock Proteins, Small / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D050888:Heat-Shock Proteins, Small