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Neurodegenerative diseases: model organisms, pathology and autophagy

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Abstract

A proteostasis view of neurodegeneration (ND) identifies protein aggregation as a leading causative reason for damage seen at the cellular and organ levels. While investigative therapies that aim at dissolving aggregates have failed, and the promises of silencing expression of ND associated pathogenic proteins or the deployment of engineered induced pluripotent stem cells (iPSCs) are still in the horizon, emerging literature suggests degrading aggregates through autophagy-related mechanisms hold the current potential for a possible cure. Macroautophagy (hereafter autophagy) is an intracellular degradative pathway where superfluous or unwanted cellular cargoes (such as peroxisomes, mitochondria, ribosomes, intracellular bacteria and misfolded protein aggregates) are wrapped in double membrane vesicles called autophagosomes that eventually fuses with lysosomes for their degradation. The selective branch of autophagy that deals with identification, capture and degradation of protein aggregates is called aggrephagy. Here, we cover the workings of aggrephagy detailing its selectivity towards aggregates. The diverse cellular adaptors that bridge the aggregates with the core autophagy machinery in terms of autophagosome formation are discussed. In ND, essential protein quality control mechanisms fail as the constituent components also find themselves trapped in the aggregates. Thus, although cellular aggrephagy has the potential to be upregulated, its dysfunction further aggravates the pathogenesis. This phenomenon when combined with the fact that neurons can neither dilute out the aggregates by cell division nor the dead neurons can be replaced due to low neurogenesis, makes a compelling case for aggrephagy pathway as a potential therapeutic option.

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Acknowledgements

We thank members of the autophagy lab (JNCASR), Mridhula Giridharan and Aparna Hebbar for critical reading of the manuscript. We apologize to researchers whose work could not be included due to constraint in space. We acknowledge Wellcome Trust/DBT India Alliance Intermediate Fellowship (500159-Z-09-Z), DST-SERB Grant (EMR/2015/001946) and LSRB-DRDO Grant (LSRB-31012017-2018) to RM, DST-SERB Grant (EMR/2015/001946) to JC, and JNCASR intramural funds.

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  1. Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bengaluru, 560 064, India

    S. N. Suresh & Ravi Manjithaya

  2. Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur, Bengaluru, 560 064, India

    Vijaya Verma, Shruthi Sateesh, James P. Clement & Ravi Manjithaya

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Suresh, S.N., Verma, V., Sateesh, S. et al. Neurodegenerative diseases: model organisms, pathology and autophagy. J Genet 97, 679–701 (2018). https://doi.org/10.1007/s12041-018-0955-3

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