Selective role of autophagy in neuronal function and neurodegenerative diseases

Abstract

·Editorial·Proteostasis is critical for neuronal maintenance and survival, and its imbalance leads to neurodegeneration with the hallmark of protein misfolding and aggregation [1] .Macroautophagy becomes a major route for the clearance of protein aggregates that are normally poor substrates for the proteasome, the other protein quality-control machinery [2] . As a fl ux process, macroautophagy (hereafter referred to as autophagy) involves the formation of the autophagosome, a double-membrane vesicle for engulfi ng unwanted cellular components such as protein aggregates, and the fusion of autophagosomes with lysosomes that contain many potent proteases for fi nal degradation [3] .In the past decades, the mechanism of autophagy has been intensively studied under starvation conditions. Autophagy is a hierarchical process involving the activation of ULK1, the initiating kinase, and many downstream events such as Beclin 1 complex activation and LC3 lipidation [3] . It has been well established that, during amino-acid starvation, mTOR, the master nutrient sensor, dissociates from and in turn activates ULK1 kinase [4] .Interestingly, upon energy starvation such as glucose depletion, the main energy sensor AMPK activates ULK1 through antagonizing mTOR-mediated ULK1 inhibitory phosphorylation [5] . It is generally believed that starvation induces non-selective autophagy that targets non-essential cellular components for degradation to provide building blocks for cellular survival in unfavorable conditions.In comparison with the well-characterized starvationinduced nonselective autophagy, the molecular mechanism of selective autophagy is largely unknown [6] . Selective autophagy is a comprehensive term that can be classifi ed into many different types such as aggrephagy, mitophagy, and lipophagy [7] . In particular, aggrephagy plays an important role in neuronal survival, as neurons are nondividing cells and cannot overcome cellular toxicity induced by protein aggregates through dilution effects. Therefore, aggrephagy becomes essential for neurons to preserve proteostasis. However, the underlying mechanism is yet to be uncovered. Recently, Huntingtin, the Huntington's disease gene product, was identifi ed as a scaffold protein for selective autophagy including aggrephagy, mitophagy, and lipophagy in mammalian cells, paving the way for further investigation in this emerging young field [8] . In addition, cargo receptor proteins such as p62 and NBR1 bring cargos to autophagosomes by interacting with the autophagosomal protein LC3 [9] . As both p62 and NBR1 contain ubiquitin-binding domains, the cargos modifi ed by lineage-specific ubiquitin play an important role in cargo recognition in selective autophagy. For instance, ubiquitin K63-modified substrates preferentially bind to p62 for autophagic degradation [10] .Selective autophagy has been linked to a variety of human diseases including but not limited to neurodegeneration and cancer [11] . For example, tau protein, implicated in Alzheimer's disease (AD), was shown to be ...

Lymphocyte Autophagy in Homeostasis, Activation, and Inflammatory Diseases

“…This selective form of macroautophagy was named lipophagy, and while it consists in a ubiquitous pathway, yet it remains poorly characterized. However, as for other forms of selective autophagic degradation, several receptors, such as huntingtin and p62, might be recruited to facilitate LD degradation ( 9 , 10 ). Increase in FFA availability is crucial to generate succinate, the primary substrate for mitochondrial β-oxidation, but also for gluconeogenesis thus creating fuel for glycolysis and so increasing adenosine tri-phosphate (ATP) level ( 11 ).…”

Dysregulation of autophagy in melanocytes contributes to hypopigmented macules in tuberous sclerosis complex

“…Despite these advances, the mechanism of autophagyregulated pigmentation is still controversial. Dysregulated autophagy has been reported in neurons as well, mTOR inhibition by rapamycin accounting for improved neuronal symptoms in patients and in mouse model alike [47]. Because melanocytes and neurons share embryonic origin [48] and both cell types are affected in TSC [27], no doubt a similar mechanism is operant.…”

BAG3 promotes autophagy and glutaminolysis via stabilizing glutaminase

“…Autophagy is an evolutionarily conserved catabolic process that is important to maintain cellular homeostasis 15 . Although autophagy was considered to be a random process for many years, accumulating data now support that it is a selective process and receives tight regulation 16 . It has been well documented that BAG3 is induced by various stressful stimuli and facilitates selective autophagy to serve as an adaptive response to maintain cellular homeostasis 7 , 8 , 10 , 13 , 17 – 22 .…”