Biomedical Implications of Autophagy in Macromolecule Storage Disorders

Abstract

An imbalance between the production and clearance of macromolecules such as proteins, lipids and carbohydrates can lead to a category of diseases broadly known as macromolecule storage disorders. These include, but not limited to, neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease associated with accumulation of aggregation-prone proteins, Lafora and Pompe disease associated with glycogen accumulation, whilst lipid accumulation is characteristic to Niemann-Pick disease and Gaucher disease. One of the underlying factors contributing to the build-up of macromolecules in these storage disorders is the intracellular degradation pathway called autophagy. This process is the primary clearance route for unwanted macromolecules, either via bulk non-selective degradation, or selectively via aggrephagy, glycophagy and lipophagy. Since autophagy plays a vital role in maintaining cellular homeostasis, cell viability and human health, malfunction of this process could be detrimental. Indeed, defective autophagy has been reported in a number of macromolecule storage disorders where autophagy is impaired at distinct stages, such as at the level of autophagosome formation, autophagosome maturation or improper lysosomal degradation of the autophagic cargo. Of biomedical relevance, autophagy is regulated by multiple signaling pathways that are amenable to chemical perturbations by small molecules. Induction of autophagy has been shown to improve cell viability and exert beneficial effects in experimental models of various macromolecule storage disorders where the lysosomal functionality is not overtly compromised. In this review, we will discuss the role of autophagy in certain macromolecule storage disorders and highlight the potential therapeutic benefits of autophagy enhancers in these pathological conditions.

Keywords: autophagy; autophagy inducers; glycogen storage disorders; lipid storage disorders; macromolecule storage disorders; neurodegenerative disorders; proteinopathies; selective autophagy.

FIGURE 1

Regulation of the mammalian autophagy pathway. Autophagy initiates by the formation of phagophore that expands and engulfs autophagic cargo to form autophagosome, which then matures to form autolysosome, either by initially fusing with the late endosome to form amphisome and then with the lysosome, or by directly fusing with the lysosome. Selective autophagic cargo includes aggregation-prone proteins, damaged mitochondria, lipid droplets and glycogen, as well as the autophagy receptor protein p62; all of which are degraded in the autolysosome. Several ATG proteins including the ATG12-ATG5-ATG16L1 complex and LC3-II mediate the initiation of autophagy. LC3-II remains on the autophagosome throughout its lifespan and is thus used as a marker for autophagy. The classical regulator of autophagy is mTORC1, which negatively regulates autophagy by inhibiting the ULK1 complex. However, AMPK can positively regulate autophagy by directly phosphorylating ULK1. The mTORC1-independent regulators of autophagy include elevated intracellular levels of IP₃, Ca²⁺, and cAMP; all of which are autophagy inhibitory signals. Autophagosome maturation in the late stage of autophagy is governed by various factors including SNAREs, HOPS complex, Rab7, GABARAPs, and ATG14L, amongst others. Autophagy can be induced pharmacologically by mTOR inhibitors (rapamycin, torin1), as well as by mTOR-independent inducers such as via AMPK activators (trehalose), and via agents lowering IP₃ (carbamazepine), Ca²⁺ (verapamil, felodipine), and cAMP (rilmenidine) levels (reduction in second messenger molecules indicated by red arrows). Abbreviations - AMPK, 5′ adenosine monophosphate-activated protein kinase; ATG, Autophagy related; Ca²⁺, Calcium; cAMP, 3′,5′-cyclic adenosine monophosphate; FIP200, FAK family kinase-interacting protein of 200 kDa; GABARAP, γ-aminobutyric acid receptor-associated protein; HOPS, Homotypic fusion and protein sorting complex; IP₃, Inositol 1,4,5-trisphosphate; mTORC1, Mechanistic target of rapamycin complex 1; SNARE, Soluble N-ethylmaleimide-sensitive factor activating protein receptor.

FIGURE 2

Impairment of autophagy in macromolecule storage disorders. Autophagy initiates by the formation of phagophore that expands and engulfs autophagic cargo to form autophagosome, which then matures to form autolysosome, either by initially fusing with the late endosome to form amphisome and then with the lysosome, or by directly fusing with the lysosome. Selective autophagic cargo includes aggregation-prone proteins, damaged mitochondria, lipid droplets and glycogen, as well as the autophagy receptor protein p62. LC3-II is used as a marker for autophagy as it remains on the autophagosome throughout its lifespan. Impairment of autophagy at distinct stages, such as autophagosome formation, cargo recognition and autophagosome maturation, caused due to the mutant proteins associated with various macromolecule storage disorders are indicated (red lines). Pharmacological induction of autophagy (blue arrow) by autophagy inducers (in blue box) exerts therapeutic benefits in transgenic models of many of these diseases. Abbreviations – AD, Alzheimer’s disease; FD, Fabry disease; FTD, Frontotemporal dementia; GD, Gaucher disease; GSDIa, Glycogen storage disease type Ia; GSDII, Glycogen storage disease type II; HD, Huntington’s disease; LD, Lafora disease; mTOR, Mechanistic target of rapamycin; NPC, Niemann-Pick type C; PD, Parkinson’s disease; PINK1, PTEN-induced kinase 1.