The impact of TP53 activation and apoptosis in primary hereditary microcephaly

Abstract

Autosomal recessive primary microcephaly (MCPH) is a constellation of disorders that share significant brain size reduction and mild to moderate intellectual disability, which may be accompanied by a large variety of more invalidating clinical signs. Extensive neural progenitor cells (NPC) proliferation and differentiation are essential to determine brain final size. Accordingly, the 30 MCPH loci mapped so far (MCPH1-MCPH30) encode for proteins involved in microtubule and spindle organization, centriole biogenesis, nuclear envelope, DNA replication and repair, underscoring that a wide variety of cellular processes is required for sustaining NPC expansion during development. Current models propose that altered balance between symmetric and asymmetric division, as well as premature differentiation, are the main mechanisms leading to MCPH. Although studies of cellular alterations in microcephaly models have constantly shown the co-existence of high DNA damage and apoptosis levels, these mechanisms are less considered as primary factors. In this review we highlight how the molecular and cellular events produced by mutation of the majority of MCPH genes may converge on apoptotic death of NPCs and neurons, via TP53 activation. We propose that these mechanisms should be more carefully considered in the alterations of the sophisticated equilibrium between proliferation, differentiation and death produced by MCPH gene mutations. In consideration of the potential druggability of cell apoptotic pathways, a better understanding of their role in MCPH may significantly facilitate the development of translational approaches.

A human-specific, concerted repression of microcephaly genes contributes to radiation-induced growth defects in forebrain organoids

“…Therefore, we analyzed gene expression profiles of the 30 known MCPH genes (6,8,9) in our organoids, both during their development and after irradiation. We found that the majority of MCPH-associated genes were significantly downregulated during organoid maturation, with the biggest changes occurring between D28 and D56 (Figure 6C).…”

“…Therapeutic approaches to prevent (radiation-induced) microcephaly currently do not exist, although many studies in mice have indicated that it can be at least partly rescued by inhibition of p53 (8,9). However, targeting p53 is not without risk, given its role in many cellular processes.…”

“…Microcephaly primary hereditary (MCPH), a non-syndromic genetic form of primary microcephaly, is the most well-characterized subtype, for which 30 genes have been identified as causative and further referred to as “MCPH genes” (6,7). These genes are involved in centrosome biogenesis and DNA repair pathways, with patients often displaying genomic instability due to DNA damage accumulation and radiosensitivity (8,9). This underscores the particular sensitivity of the developing brain to DNA damage, which is further illustrated by the fact that DNA repair deficiency syndromes often display microcephaly as one of the most prominent features (8,10).…”

Autosomal recessive primary microcephaly type 2 associated with a novel WDR62 splicing variant that disrupts the expression of the functional transcript

“…Due to the wide variety of primary microcephaly subtypes ( 2 , 23 , 24 ), we utilized WES to streamline the diagnostic procedure. The inheritance pattern indicated an autosomal recessive trait.…”

Causes of microcephaly in human—theoretical considerations

“…In many cases, such impairment comes along with reduced survival of CSPSc. Thus, mutations in genes causing autosomal recessive primary microcephaly (MCPH) often lead to apoptotic death not only of CSPCs, but also of cortical neurons (Legiani et al, 2023). However, neuronal apoptosis can also be caused by mutations in genes expressed in, or specifically relevant for, neurons but not CSPCs.…”