Mitotic defects lead to neuronal aneuploidy and apoptosis in frontotemporal lobar degeneration caused by MAPT...

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Mutations in the MAPT gene are linked to frontotemporal lobar degeneration (FTLD).
• Previous research suggests MAPT mutations correlate with aneuploidy and chromosome instability.
• The role of MAPT mutations in inducing brain cell aneuploidy and apoptosis in FTLD remains unclear.

Purpose of the Study:

• To investigate if FTLD-associated MAPT mutations induce aneuploidy and apoptosis in the mammalian brain.
• To determine the relationship between MAPT mutations, aneuploidy, and neurodegeneration in FTLD.
• To elucidate the cellular mechanisms linking MAPT mutations to apoptosis.

Main Methods:

• Analysis of brain cells from MAPT mutant transgenic mice and tau (Mapt) null mice.
• Measurement of aneuploidy and apoptosis in brain cells from FTLD patients with MAPT mutations.
• Expression of FTLD-causing mutant MAPT in karyotypically normal human cells to assess aneuploidy and mitotic defects.

Main Results:

• Aneuploidy was detected in brain cells of MAPT mutant mice.
• Decreasing tau (Mapt) gene dosage correlated with increasing aneuploidy in mouse neurons.
• Increased aneuploidy and apoptosis were observed in neurons and glia from FTLD patients with MAPT mutations.
• Expression of mutant MAPT induced aneuploidy, mitotic spindle defects, and subsequent apoptosis in human cells.

Conclusions:

• FTLD-causing MAPT mutations trigger a neurodegenerative pathway involving mitotic spindle abnormalities, chromosome mis-segregation, and aneuploidy.
• This aneuploidy and chromosomal instability subsequently lead to apoptosis in neurons and glia.
• The findings establish a direct link between MAPT mutations, aneuploidy, and neurodegeneration in FTLD.