Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases

• Published in: Journal of molecular biology 2020-04, Vol.432 (8), p.2799-2821
• Main Authors: Djajadikerta, Alvin, Keshri, Swati, Pavel, Mariana, Prestil, Ryan, Ryan, Laura, Rubinsztein, David C.
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; amyotrophic lateral sclerosis; Animals; Autophagy; Autophagy-Related Proteins - metabolism; Humans; lysosome; Molecular Targeted Therapy; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurodegenerative Diseases - therapy; Parkinson’s disease; polyglutamine diseases; Signal Transduction
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2019.12.035

Autophagy is a major, conserved cellular pathway by which cells deliver cytoplasmic contents to lysosomes for degradation. Genetic studies have revealed extensive links between autophagy and neurodegenerative disease, and disruptions to autophagy may contribute to pathology in some cases. Autophagy degrades many of the toxic, aggregate-prone proteins responsible for such diseases, including mutant huntingtin (mHTT), alpha-synuclein (α-syn), tau, and others, raising the possibility that autophagy upregulation may help to reduce levels of toxic protein species, and thereby alleviate disease. This review examines autophagy induction as a potential therapy in several neurodegenerative diseases—Alzheimer’s disease, Parkinson’s disease, polyglutamine diseases, and amyotrophic lateral sclerosis (ALS). Evidence in cells and in vivo demonstrates promising results in many disease models, in which autophagy upregulation is able to reduce the levels of toxic proteins, ameliorate signs of disease, and delay disease progression. However, the effective therapeutic use of autophagy induction requires detailed knowledge of how the disease affects the autophagy-lysosome pathway, as activating autophagy when the pathway cannot go to completion (e.g., when lysosomal degradation is impaired) may instead exacerbate disease in some cases. Investigating the interactions between autophagy and disease pathogenesis is thus a critical area for further research. [Display omitted] •Autophagy delivers cytoplasmic cargoes to lysosomes for degradation.•It degrades many aggregate-prone proteins responsible for neurodegenerative disease.•Enhancing autophagy has therapeutic potential in common neurodegenerative diseases.•Evidence in cells and in vivo demonstrates promising results in many disease models.•Outcomes may depend on how autophagy impacts disease pathogenesis.