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Quality Control in Huntington’s Disease: a Therapeutic Target

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Abstract

Huntington’s disease (HD) is a fatal autosomal dominantly inherited brain disease caused by excessively expanded CAG repeats in gene which encodes huntingtin protein. These abnormally encoded huntingtin proteins and their truncated fragments result in disruption of cellular quality mechanism ultimately triggering neuronal death. Despite great efforts, a potential causative agent leading to genetic mutation in HTT, manifesting the neurons more prone to oxidative stress, cellular inflammation, energy depletion and apoptotic death, has not been established yet. Current scenario concentrates on symptomatic pathologies to improvise the disease progression and to better the survival. Most of the therapeutic developments have been converged to rescue the protein homeostasis. In HD, abnormal expansion of glutamine repeats in the protein huntingtin leads to toxic aggregation of huntingtin which in turn impairs the quality control mechanism of cells through damaging the machineries involved in removal of aggregated abnormal protein. Therapeutic approaches to improve the efficiency of aggregate clearance through quality control mechanisms involve protein folding machineries such as chaperones and protein degradation machineries such as proteasome and autophagy. Also, to reduce protein aggregation by enhancing proper folding, to degrade and eliminate the aggregates are suggested to negatively regulate the HD progression associated with the disruption of protein homeostasis. This review focuses on the collection of therapeutic strategies targeting enhancement of protein quality control activity to delay the HD pathogenesis.

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  1. Sachchida Nand Rai and Brijesh Kumar Singh contributed equally to this work.

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  1. Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, India

    Sachchida Nand Rai, Aaina Singh Rathore, Walia Zahra, Chetan Keswani, Hareram Birla, Saumitra Sen Singh, Hagera Dilnashin & Surya Pratap Singh

  2. Department of Pathology and Cell Biology, Columbia University Medical Centre, Columbia University, New York, NY, 10032, USA

    Brijesh Kumar Singh

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Rai, S.N., Singh, B.K., Rathore, A.S. et al. Quality Control in Huntington’s Disease: a Therapeutic Target. Neurotox Res 36, 612–626 (2019). https://doi.org/10.1007/s12640-019-00087-x

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