Targeting autophagy in neurodegenerative diseases: From molecular mechanisms to clinical therapeutics

Abstract

Many neurodegenerative diseases are associated with pathological aggregation of proteins in neurons. Autophagy is a natural self-cannibalization process that can act as a powerful mechanism to remove aged and damaged organelles as well as protein aggregates. It has been shown that promoting autophagy can attenuate or delay neurodegeneration by removing protein aggregates. In this paper, we will review the role of autophagy in Alzheimer's disease (AD), Parkinson's Disease (PD), and Huntington's Disease (HD) and discuss opportunities and challenges of targeting autophagy as a potential therapeutic avenue for treatment of these common neurodegenerative diseases.

Keywords: Alzheimer's disease; Huntington's disease; Parkinson's disease; autophagy; neurodegenerative disease.

Figure 1.

Various neuronal stresses such as nutrient deprivation and ROS trigger diverse pathways that regulate autophagy. Deprivation of amino acids and glucose substantially accelerate cytosolic level of AMP and Ca²⁺ in neurons. Enhanced AMP level triggers activation of AMPK (master regulator of autophagy), which upregulates ATG genes, blocks MTORC1, and activates ULK1, ultimately leading to autophagy initiation. Increased cytosolic level of Ca²⁺ also mediates AMPK activation and mitochondrial depolarization, which accounts for ROS production. ROS, in turn, activates certain transcriptional factors and AMPK thus, leading to autophagy. Eventually, ATG proteins are recruited to various steps of phagophore and autophagosome formation, resulting in clearance of protein aggregates and impaired organelles via fusion with lysosome. Although basal autophagy alleviates neurodegeneration, its excessive induction may lead to various styles of cell death ^,,,. Abbreviations: DAPK (death associated protein kinase), CAMKK2 (calcium/calmodulin dependent protein kinase kinase 2), JUN/C-Jun (Jun proto-oncogene, AP-1 transcription factor subunit), FUNDC1 (FUN14 domain containing 1), Ub (ubiquitin), AMP (adenosine monophosphate), HIF1A/HIF1α (hypoxia inducible factor 1 subunit alpha), RPTOR/raptor (regulatory associated protein of MTOR complex 1), MAPK8/JNK1 (mitogen-activated protein kinase 8), DDIT4 (DNA damage inducible transcript 4), PIK3R4/VPS15 (phosphoinositide-3-kinase regulatory subunit 4), DRAM (DNA damage regulated autophagy modulator), RB1CC1/FIP200 (RB1 inducible coiled-coil 1), BNIP3 (BCL2 interacting protein 3).

Figure 2.

Holistic strategies for targeting autophagy in the management of neurodegenerative diseases. Natural autophagy inducers manipulate autophagy regulators via various mechanisms, leading to basal autophagy induction (likely, in a dose dependent manner). Numerous studies have substantiated the vital role of physical exercise and caloric restriction as non-invasive strategies for autophagy induction ^,–. Abbreviations: NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2), FOXO3 (forkhead box O3), SIRT3 (sirtuin 3), RAB7 (RAB7, member RAS oncogene family), VDAC1 (voltage dependent anion channel 1), MAPK1/3 (mitogen-activated protein kinase 1/3), MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta)