Endoplasmic reticulum and Golgi stress in microcephaly

Abstract

Microcephaly is a neurodevelopmental condition characterized by a small brain size associated with intellectual deficiency in most cases and is one of the most frequent clinical sign encountered in neurodevelopmental disorders. It can result from a wide range of environmental insults occurring during pregnancy or postnatally, as well as from various genetic causes and represents a highly heterogeneous condition. However, several lines of evidence highlight a compromised mode of division of the cortical precursor cells during neurogenesis, affecting neural commitment or survival as one of the common mechanisms leading to a limited production of neurons and associated with the most severe forms of congenital microcephaly. In this context, the emergence of the endoplasmic reticulum (ER) and the Golgi apparatus as key guardians of cellular homeostasis, especially through the regulation of proteostasis, has raised the hypothesis that pathological ER and/or Golgi stress could contribute significantly to cortical impairments eliciting microcephaly. In this review, we discuss recent findings implicating ER and Golgi stress responses in early brain development and provide an overview of microcephaly-associated genes involved in these pathways.

ERAD components Derlin-1 and Derlin-2 are essential for postnatal brain development and motor function

“…We speculate that these motor deficits are due to insufficient processing capacity by motor control circuits comprising these maldeveloped striatal and cerebellar neurons. An alternative explanation is that Derlin perturbs the UPR, which has also been reported to induce severe brain maldevelopment ( Alimov et al., 2013 ; Passemard et al., 2019 ). However, we suggest that an ER stress response triggered by impaired ER quality control does not contribute to the observed postnatal brain atrophy in Derlin-deficient mice because the treatment of primary Derlin-1-deficient neurons with 4-PBA did not mitigate the shortened neurite outgrowth ( Figure 4 F).…”

Podophyllotoxin Exposure Affects Organelle Distribution and Functions in Mouse Oocyte Meiosis

“…And the depletion of GM130, a cis- Golgi protein, could disturb spindle organization, migration, and asymmetric division during mouse oocyte maturation ( Zhang et al, 2011 ). Moreover, the Golgi apparatus is often affected by the ER due to its role in post-translational modifications and transport of newly synthesized proteins and lipids ( Passemard et al, 2019 ). Our results show that POD led to a failure of spindle periphery accumulation of the Golgi apparatus in mouse oocytes.…”

Heme oxygenase-1(HO-1) regulates Golgi stress and attenuates endotoxin-induced acute lung injury through hypoxia inducible factor-1α (HIF-1α)/HO-1 signaling pathway

“…Golgi dispersal may be a kind of compromise response for cellular stress resistance, because its membranes will lose some antioxidant molecules and some factors crucial for redox homeostasis, which could propagate Golgi-derived lipid peroxides[ 45 ].Under some toxic conditions, Golgi membranes can produce some lethal lipid ROS species, which could be transported to other compartments[ 45 ]. Recently, more and more research have found that oxidative stress can also affect the structure and normal physiological function of the GA[ 1 , 5 , 46 ]. ROS can not only impair Golgi-associated vesicular trafficking and protein sorting processes, but also influence glycosylation[ 47 ].…”