Differential regulation of small heat shock proteins in transgenic mouse models of neurodegenerative diseases

Jiou Wang, Elizabeth Martin, Victoria Gonzales, David R. Borchelt, Michael K. Lee

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45 Scopus citations


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 α-synuclein (α-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 αB-crystallin, were differentially regulated in these mice. Levels of both Hsp25 and αB-crystallin were markedly increased in subgroups of glias at the affected regions of symptomatic SODG37R and α-SynA53T transgenic mice; abnormal deposits or cells intensely positive for αB-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 αB-crystallin in spinal cords gradually increased as a function of age in nontransgenic animals. In vitro, αB-crystallin was capable of suppressing the aggregation of α-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.

Original languageEnglish (US)
Pages (from-to)586-597
Number of pages12
JournalNeurobiology of Aging
Issue number4
StatePublished - Apr 2008

Bibliographical note

Funding Information:
We thank Drs. Juan Troncoso and Lee Martin for their help with the sHSP pathology and cellular identification. We also thank Michael Coonfield and Yanqun Xu for the technical assistance with the transgenic mice. This study was supported by grants to DRB (NS044278) and MKL (NS38065, NS38377) from the National Institutes of Neurologic Disease and Stroke (R01 NS 044278), the Muscular Dystrophy Association (DRB), the ALS Association (DRB), and by the Robert Packard Center for ALS Research at The Johns Hopkins University (DRB).


  • Aging
  • Hsp25
  • Neurodegeneration
  • αB-crystallin


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