Mendelian neurodegenerative disease genes involved in autophagy

Abstract

The lysosomal degradation pathway of macroautophagy (herein referred to as autophagy) plays a crucial role in cellular physiology by regulating the removal of unwanted cargoes such as protein aggregates and damaged organelles. Over the last five decades, significant progress has been made in understanding the molecular mechanisms that regulate autophagy and its roles in human physiology and diseases. These advances, together with discoveries in human genetics linking autophagy-related gene mutations to specific diseases, provide a better understanding of the mechanisms by which autophagy-dependent pathways can be potentially targeted for treating human diseases. Here, we review mutations that have been identified in genes involved in autophagy and their associations with neurodegenerative diseases. LC3/GABARAP family protein lipidation. The core ATG proteins are necessary, but not sufficient for degradative autophagy (Fig. 1). Autophagosomal degradation cannot proceed without successful fusion to functional lysosomes. Research in the past decade has unmasked several key factors required for autophagolysosomal fusion, such as the GABARAP subfamily, as well as the CORVET-HOPS and the STX17-SNAP29-VAMP8/ VAMP7 SNARE complexes 2-5 .

Autophagy in Multiple Sclerosis: Two Sides of the Same Coin

“…Different types of autophagy have been described based on their differences in regulation, type of cargo, and the lysosomal delivery mechanism: chaperone-mediated autophagy, microautophagy, and macroautophagy (Feng et al, 2018). These processes are described in detail elsewhere (Martinez-Vicente and Cuervo, 2007;Cuervo, 2010;Li et al, 2012;Feng et al, 2014) and here we focus on the regulation of macroautophagy since this process is best described in brain disorders (Nixon, 2013;Liang and Le, 2015;Menzies et al, 2017;van Beek et al, 2018;Yin et al, 2018;Levine and Kroemer, 2019;Stamatakou et al, 2020).…”

Autophagy regulation by acetylation—implications for neurodegenerative diseases

“…In mammalian cells, autophagosomes are formed from cup-shaped precursor structures called phagophores, which include a complex of autophagy proteins, including ATG5, ATG12 and ATG16L1 2 . The membranes of phagophores expand and form enclosed autophagosomes, and completed autophagosomes subsequently fuse with lysosomes 2 , 3 . Lysosomal digestion of autophagic cargoes protects cells against starvation and related stresses by releasing recycled building blocks from autophagic substrates.…”

“…Under normal conditions, cells sustain basal levels of autophagy to maintain homeostasis. However, a variety of stimuli, including nutrient deprivation, metabolic imbalance or cellular stress, can activate autophagy 2 , 3 . Autophagosome biogenesis includes three early stages: initiation, nucleation, and expansion of the isolation membrane (Fig.…”

Simvastatin accelerated motoneurons death in SOD1G93A mice through inhibiting Rab7-mediated maturation of late autophagic vacuoles

“…In fact, nascent APs are capable of trafficking to the lysosome and fusing with early or late phase endosomes/lysosomes and subsequent forming degradative autolysosomes, a process known as AP maturation 8 . The small GTP binding protein Rab7 is a member of the Rab family that has been required for late endosomal/autophagosomal transport and finally participated in the fusion step with lysosomes 9 – 11 . Neurons appear to be particularly dependent on autophagy 12 .…”