Autophagy deficiency in neurodevelopmental disorders

Abstract

Autophagy is a cell self-digestion pathway through lysosome and plays a critical role in maintaining cellular homeostasis and cytoprotection. Characterization of autophagy related genes in cell and animal models reveals diverse physiological functions of autophagy in various cell types and tissues. In central nervous system, by recycling injured organelles and misfolded protein complexes or aggregates, autophagy is integrated into synaptic functions of neurons and subjected to distinct regulation in presynaptic and postsynaptic neuronal compartments. A plethora of studies have shown the neuroprotective function of autophagy in major neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). Recent human genetic and genomic evidence has demonstrated an emerging, significant role of autophagy in human brain development and prevention of spectrum of neurodevelopmental disorders. Here we will review the evidence demonstrating the causal link of autophagy deficiency to congenital brain diseases, the mechanism whereby autophagy functions in neurodevelopment, and therapeutic potential of autophagy.

The paradigm of amyloid precursor protein in amyotrophic lateral sclerosis: The potential role of the 682YENPTY687 motif

“…In addition, YG mice display a progressive reduction in muscular strength, motor functions and abilities, and learning performance [157] . Such deficits are associated with age-dependent cognitive decline, autophagic dysfunction, and progressive dendritic spine loss [125] , mirroring some of the crucial features reported in patients [158] ( Fig. 1 ).…”

Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship

“…Recently, a functional enrichment analysis obtained from a cross-ancestry genome-wide association study found a group of enriched genes involved in membrane trafficking, Golgi-to-ER trafficking, and autophagy within ALS-associated loci [ 82 ]. This result further tethers ALS to MAMs modulation of autophagic/mitophagic processes, already described with other ALS experimental paradigms [ 83 ].…”

Metabolic regulation of the neural stem cell fate: Unraveling new connections, establishing new concepts

“…It has also been shown that bi-allelic null mutations in p62 present with early-onset neurodegenerative disorders (Haack et al, 2016;Muto et al, 2018). Specifically, it resulted in a dramatic increase of lactate dehydrogenase A (LDHA) expression, which correlated with deficient neurodifferentiation due to the inability to upregulate genes important for OXPHOS (Calvo-Garrido et al, 2019), a phenotype rescuable by N-acetylcysteine, suggesting a role of p62 in oxygen sensing or ROS management and implying the role of autophagy in brain-related disorders (Lee et al, 2013;Deng et al, 2021). It is known that under oxidative stress p62 stabilizes Nrf2 (Jain et al, 2010;Komatsu et al, 2010).…”