Proteostasis failure and mitochondrial dysfunction contribute to chromosomal instability-induced microcephaly

Area of Science:

• Developmental Biology
• Genetics
• Cell Biology

Background:

• Mosaic variegated aneuploidy (MVA) is a rare human congenital disorder causing microcephaly.
• It is characterized by extensive chromosome number abnormalities, stemming from mutations in genes critical for mitotic chromosome segregation.

Purpose of the Study:

• To investigate the cellular mechanisms underlying MVA-associated microcephaly.
• To establish a Drosophila model for studying MVA by depleting a spindle assembly checkpoint (SAC) gene in neural stem cells (NSCs).

Main Methods:

• Generation of a Drosophila model with depleted SAC gene in neural stem cells.
• Analysis of neural stem cell (NSC) stemness, proliferation, and differentiation.
• Investigation of the role of proteostasis and mitochondrial function in aneuploidy's effects.

Main Results:

• Loss of NSC stemness, characterized by compromised identity and proliferation, contributes to MVA.
• This loss of stemness results from accumulated complex aneuploidies, not direct DNA damage or simple aneuploidies.
• Proteostasis failure and mitochondrial dysfunction exacerbate the negative impact of aneuploidy on stemness.

Conclusions:

• Loss of neural stem cell (NSC) stemness is a key cellular mechanism in MVA.
• Complex aneuploidies, proteostasis failure, and mitochondrial dysfunction collectively impair brain development in MVA.
• Genetic interventions targeting ROS, mitochondrial chaperones, and apoptosis show potential for mitigating MVA's effects.