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Cell toxicity and conformational disease.

Robin W Carrell1

  • 1Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK CB2 2XY. rwc1000@cam.ac.uk

Trends in Cell Biology
|October 6, 2005
PubMed
Summary

Protein misfolding causes neurodegenerative diseases like Alzheimer's. Cytotoxicity arises from early aggregation stages, not just amyloid, highlighting intracellular processes and the need to study these mechanisms.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pathology

Background:

  • Late-onset neurodegenerative diseases stem from protein misfolding and aggregation.
  • Research has overemphasized extracellular amyloid deposits, neglecting intracellular disease mechanisms.

Purpose of the Study:

  • To shift focus to intracellular protein aggregation as a primary driver of neurodegeneration.
  • To investigate the cytotoxic mechanisms preceding amyloid formation.

Main Methods:

  • Analysis of structural findings in proteinopathies.
  • Review of studies on Alzheimer's disease and other dementias.
  • Examination of intracellular accumulation of misfolded proteins (e.g., alpha-1-antitrypsin, neuroserpin).

Main Results:

  • Cytotoxicity can occur from minor protein conformational changes without amyloid formation.
  • Intracellular accumulation of misfolded proteins in organelles like the endoplasmic reticulum is cytotoxic.
  • Damage in diseases like Alzheimer's initiates at early intermolecular linkage stages before amyloid.

Conclusions:

  • Intracellular protein aggregation, not solely amyloid, is key to neurodegenerative disease pathogenesis.
  • Understanding early aggregation events is crucial for elucidating disease mechanisms.
  • Further research is needed to detail the mechanisms of intracellular cytotoxicity in proteinopathies.

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