Heteroplasmic mitochondrial DNA mutations in frontotemporal lobar degeneration

Area of Science:

• Neuroscience
• Genetics
• Mitochondrial Biology

Background:

• Frontotemporal lobar degeneration (FTLD) is a significant cause of dementia in younger individuals.
• FTLD is characterized by focal neuropathology, but the reasons for regional neuronal vulnerability remain unclear.
• Mitochondrial dysfunction is suspected in FTLD pathogenesis, with potential contributions from mitochondrial DNA (mtDNA) mutations.

Purpose of the Study:

• To investigate the role of mitochondrial DNA variants in the regional vulnerability observed in FTLD.
• To identify and quantify single nucleotide variants (mtSNVs) and rearrangements in mtDNA within post-mortem brain tissue of FTLD patients and controls.

Main Methods:

• High-depth dual sequencing of the entire mitochondrial genome was performed on post-mortem brain tissue.
• Analysis focused on identifying high-fidelity single nucleotide variants (mtSNVs) and mtDNA rearrangements.
• Comparison was made between tissue from individuals with FTLD and age-matched controls.

Main Results:

• Both mtSNVs and mtDNA rearrangements were found at higher levels in the temporal lobe, particularly in FTLD cases.
• mtSNVs present in multiple brain regions showed increased heteroplasmy levels in the temporal lobe of FTLD patients.
• The temporal lobe in FTLD cases exhibited a greater burden of variants in ribosomal genes affecting protein synthesis and missense variants in respiratory chain genes.

Conclusions:

• Heteroplasmic mtDNA variants impacting oxidative phosphorylation are enriched in the temporal lobe of FTLD patients.
• These mtDNA variants are likely contributors to the specific regional vulnerability of neurons in the temporal lobe during FTLD pathogenesis.