Protein Quality Control in Neurodegeneration and Neuroprotection

Protein Quality Control in Neurodegeneration and Neuroprotection

Yasmeena Akhter, Jahangir Nabi, Hinna Hamid, Nahida Tabassum, Faheem Hyder Pottoo, Aashish Sharma
Copyright: © 2020 |Pages: 24
DOI: 10.4018/978-1-7998-1317-0.ch001
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Abstract

Proteostasis is essential for regulating the integrity of the proteome. Disruption of proteostasis under some rigorous conditions leads to the aggregation and accumulation of misfolded toxic proteins, which plays a central role in the pathogenesis of protein conformational disorders. The protein quality control (PQC) system serves as a multi-level security system to shield cells from abnormal proteins. The intrinsic PQC systems maintaining proteostasis include the ubiquitin-proteasome system (UPS), chaperon-mediated autophagy (CMA), and autophagy-lysosome pathway (ALP) that serve to target misfolded proteins for unfolding, refolding, or degradation. Alterations of PQC systems in neurons have been implicated in the pathogenesis of various neurodegenerative disorders. This chapter provides an overview of PQC pathways to set a framework for discussion of the role of PQC in neurodegenerative disorders. Additionally, various pharmacological approaches targeting PQC are summarized.
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Pathways For Removal Of Aberrant Proteins

The classic characteristic of neurodegenerative disorders is the accumulation of soluble functional protein aggregates in the central nervous system (CNS). These protein-related disorders can be found both intracellularly and extracellularly in the endoplasmic reticulum (ER), nucleus and cytosol. During the 1980s, it was assumed that only the lysosomal pathway is involved in the disposal of aggregated proteins (Yang and Klionsky, 2010). There was not much definition of the role of other arms of PQC, as the proteasome and cytoplasmic proteases were deemed only to target cytoplasmic substrates. Also, there was no reason to think that these elements would contribute to PQC-based events, particularly given the central position of the lysosome as a component of the secretory pathway (Figure 1).

Figure 1.

Degradation of misfolded proteins by protein quality control system

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