A pivotal contribution of proteostasis failure and mitochondrial dysfunction to chromosomal instability-induced microcephaly

Mosaic variegated aneuploidy (MVA), a rare human congenital disorder that causes microcephaly, is characterized by extensive abnormalities in chromosome number and results from mutations in genes involved in accurate mitotic chromosome segregation. To characterize the cellular mechanisms underlying this disease, here we generated a Drosophila model of microcephaly caused by the depletion of a single spindle assembly checkpoint (SAC) gene in the neural stem cell (NSC) compartment. We present evidence that loss of stemness - compromised identity and proliferative capacity of NSCs- is the underlying cause of MVA and results in a reduced number of neurons and glial cells. We show that loss of stemness arises from the accumulation over time of an unbalanced number of gains and losses of more than one chromosome, rather than a direct consequence of chromosomal instability-induced DNA damage or the production of simple aneuploidies. We unravel that the negative impact of complex aneuploidies on stemness, a highly energy demanding cellular state, is a result of proteostasis failure and mitochondrial dysfunction. We identify autophagy activation--either directly or through TOR depletion--, overexpression of Radical Oxygen Species scavengers, and restoration of mitochondria proteostasis as genetic interventions capable of dampening the deleterious effects of aneuploidy on NSC identity and brain development. HighlightsSAC depletion in NSCs induces microcephaly through the production of complex aneuploidies Complex aneuploidies compromise the stemness of NSCs Loss of stemness results from proteostasis failure and mitochondrial dysfunction Boosting proteostasis or mitochondria homeostasis mitigate the negative effects on NSCs eTOC BlurbDepletion of the spindle assembly checkpoint in the neural stem cell compartment leads to microcephaly. Gonzalez-Blanco et al. provide evidence that proteostasis failure and mitochondrial dysfunction play a pivotal role in causing microcephaly by compromising the stemness of highly aneuploid neural stem cells.