Tissue-Specific Vulnerability to Apoptosis in Machado-Joseph Disease

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Machado-Joseph disease (MJD) is a neurodegenerative disorder caused by CAG repeat expansion in the ATXN3 gene.
• MJD disrupts cellular processes, including transcription and apoptosis.
• Investigating apoptosis gene expression in MJD may reveal disease biomarkers.

Purpose of the Study:

• To assess dysregulation of mitochondrial apoptosis in MJD.
• To evaluate specific apoptosis gene/protein expression as potential transcriptional biomarkers.
• To analyze BCL2, BAX, and TP53 expression and the BCL2/BAX ratio in MJD subjects and a mouse model.

Main Methods:

• Quantified BCL2, BAX, and TP53 transcript levels in blood and post-mortem brain samples.
• Assessed the BCL2/BAX ratio as an indicator of apoptosis susceptibility.
• Utilized MJD subjects, MJD transgenic mice, and control groups.
• Conducted a follow-up study on 18 MJD patients over time.

Main Results:

• Reduced blood BCL2 transcripts in patients showed low discrimination accuracy.
• Increased blood BAX transcripts and decreased BCL2/BAX ratio correlated with earlier MJD onset.
• MJD brains exhibited increased BCL2/BAX ratios in specific regions, indicating apoptosis resistance.
• Blood BCL2 and TP53 transcripts increased over time in MJD patients.

Conclusions:

• Tissue-specific apoptosis vulnerability exists in MJD.
• The MJD mouse model partially replicates human disease gene expression profiles.
• Blood BAX and BCL2/BAX ratio changes may associate with MJD pathogenesis and onset.
• Apoptosis gene expression patterns offer insights into MJD pathophysiology.