Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration

Nat Commun. 2013;4:1405. doi: 10.1038/ncomms2417.

Abstract

A crucial feature of adult-onset neurodegenerative diseases is accumulation of abnormal protein in specific brain regions, although the mechanism underlying this pathological selectivity remains unclear. Heat shock factor-1 is a transcriptional regulator of heat shock proteins, molecular chaperones that abrogate neurodegeneration by refolding and solubilizing pathogenic proteins. Here we show that heat shock factor-1 expression levels are associated with the accumulation of pathogenic androgen receptor in spinal and bulbar muscular atrophy, a polyglutamine-induced neurodegenerative disease. In heterozygous heat shock factor-1-knockout spinal and bulbar muscular atrophy mice, abnormal androgen receptor accumulates in the cerebral visual cortex, liver and pituitary, which are not affected in their genetically unmodified counterparts. The depletion of heat shock factor-1 also expands the distribution of pathogenic androgen receptor accumulation in other neuronal regions. Furthermore, lentiviral-mediated delivery of heat shock factor-1 into the brain of spinal and bulbar muscular atrophy mice topically suppresses the pathogenic androgen receptor accumulation and neuronal atrophy. These results suggest that heat shock factor-1 influences the pathological lesion selectivity in spinal and bulbar muscular atrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Central Nervous System / metabolism
  • Central Nervous System / pathology
  • DNA-Binding Proteins / metabolism*
  • HEK293 Cells
  • Heat Shock Transcription Factors
  • Heat-Shock Proteins / metabolism
  • Heterozygote
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Motor Cortex / drug effects
  • Motor Cortex / metabolism
  • Motor Cortex / pathology
  • Muscular Disorders, Atrophic / metabolism
  • Muscular Disorders, Atrophic / pathology
  • Mutant Proteins / metabolism
  • Neostriatum / drug effects
  • Neostriatum / metabolism
  • Neostriatum / pathology
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Organ Specificity / drug effects
  • Peptides / toxicity*
  • Pituitary Gland / metabolism
  • Receptors, Androgen / metabolism
  • Transcription Factors / metabolism*
  • Transgenes

Substances

  • DNA-Binding Proteins
  • Heat Shock Transcription Factors
  • Heat-Shock Proteins
  • Hsf1 protein, mouse
  • Mutant Proteins
  • Peptides
  • Receptors, Androgen
  • Transcription Factors
  • polyglutamine