Polyglutamine aggregation in Huntington's disease and spinocerebellar ataxia type 3: similar mechanisms in aggregate formation

K. Seidel*, S. Siswanto, M. Fredrich, M. Bouzrou, E. R. Brunt, F. W. van Leeuwen, H. H. Kampinga, H. -W. Korf, U. Rueb, W. F. A. den Dunnen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

22 Citations (Scopus)

Abstract

AimsPolyglutamine (polyQ) diseases are characterized by the expansion of a polymorphic glutamine sequence in disease-specific proteins and exhibit aggregation of these proteins. This is combated by the cellular protein quality control (PQC) system, consisting of chaperone-mediated refolding as well as proteasomal and lysosomal degradation pathways. Our recent study in the polyQ disease spinocerebellar ataxia type 3 (SCA3) suggested a distinct pattern of protein aggregation and PQC dysregulation.

MethodsTo corroborate these findings we have investigated immunohistochemically stained 5m sections from different brain areas of Huntington's disease (HD) and SCA3 patients.

ResultsIrrespective of disease and brain region, we observed peri- and intranuclear polyQ protein aggregates. A subset of neurones with intranuclear inclusions bodies exhibited signs of proteasomal dysfunction, up-regulation of HSPA1A and re-distribution of DNAJB1. The extent of the observed effects varied depending on brain area and disease protein.

ConclusionsOur results suggest a common sequence, in which formation of cytoplasmic and nuclear inclusions precede proteasomal impairment and induction of the cellular stress response. Clearly, impairment of the PQC is not the primary cause for inclusion formation, but rather a consequence that might contribute to neuronal dysfunction and death. Notably, the inclusion pathology is not directly correlated to the severity of the degeneration in different areas, implying that different populations of neurones respond to polyQ aggregation with varying efficacy and that protein aggregation outside the neuronal perikaryon (e.g. axonal aggregates) or other effects of polyQ aggregation, which are more difficult to visualize, may contribute to neurodegeneration.

Original languageEnglish
Pages (from-to)153-166
Number of pages14
JournalNeuropathology and Applied Neurobiology
Volume42
Issue number2
Early online date11-Jun-2015
DOIs
Publication statusPublished - Feb-2016

Keywords

  • Huntington's disease
  • polyglutamine
  • protein aggregation
  • protein quality control
  • spinocerebellar ataxia
  • NEURONAL INTRANUCLEAR INCLUSIONS
  • DOMINANT CEREBELLAR ATAXIAS
  • MACHADO-JOSEPH-DISEASE
  • EXPANDED POLYGLUTAMINE
  • CLINICAL-FEATURES
  • PROTEIN
  • P62/SQSTM1
  • AUTOPHAGY
  • DEATH
  • NEUROPATHOLOGY

Cite this