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Polyglutamine-mediated aggregation and cell death
T de Cristofaro1, A Affaitati, A Feliciello
1Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli "Federico II", Via Pansini 5, Naples, Italy.
Biochemical and Biophysical Research Communications
|June 22, 2000
Summary
CAG repeat expansion causes neurodegenerative diseases, leading to protein aggregates. These nuclear aggregates trigger cell death (apoptosis) and suggest protein degradation pathways are crucial for survival in these conditions.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- CAG repeat expansion is the genetic cause of eight neurodegenerative diseases.
- Intracellular aggregates in neurons are a common hallmark, but their role in neurodegeneration is unclear.
Purpose of the Study:
- To investigate the role of CAG repeat expansion and subsequent protein aggregation in neuronal cell death.
- To determine if nuclear aggregates directly induce apoptosis.
Main Methods:
- Constructed a synthetic fusion protein with 17 (normal) or 43 (expanded) CAG repeats linked to green fluorescent protein.
- Expressed the fusion protein in human neuroblastoma cells.
- Observed aggregate formation, cell proliferation, and apoptosis.
Main Results:
- Expression of 43 CAG repeats, but not 17, formed nuclear aggregates in neuroblastoma cells.
- Normal 17 CAG repeats were sequestered into inclusion bodies with expanded repeats.
- Nuclear aggregate formation strongly correlated with apoptosis; cells with aggregates ceased proliferation and died.
- Inhibiting protein degradation pathways increased aggregates and cell death.
Conclusions:
- Intranuclear aggregates induced by expanded CAG repeats directly trigger apoptosis.
- The degradation of unfolded proteins is essential for cell survival in CAG repeat expansion disorders.