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      https://www.ias.ac.in/article/fulltext/jgen/097/03/0679-0701

    • Keywords

       

      neurodegeneration; aggrephagy; small molecule therapeutics

    • 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 combinedwith 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.

    • Author Affiliations

       

      S. N. SURESH1 VIJAYA VERMA2 SHRUTHI SATEESH2 JAMES P. CLEMENT2 RAVI MANJITHAYA1 2

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

       
  • Journal of Genetics | News

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