Neurodegenerative diseases are a class of age-associated proteopathies characterized
by the accumulation of misfolded and/or aggregation-prone proteins. This imbalance
has been attributed, in part, to an age-dependent decay in the capacity of protein
turnover. Most proteins are degraded by the ubiquitin-proteasome system (UPS), which
is composed of ubiquitin ligases and regulatory particles, such as the 19S, that deliver
cargo to the proteolytically active 20S proteasome (20S) core. However, a subset of
clients, especially intrinsically disordered proteins (IDPs), are also removed by
the action of the ubiquitin-independent proteasome system (UIPS). What are the specific
contributions of the UPS and UIPS in the context of neurodegeneration? Here, we explore
how age-associated changes in the relative contribution of the UPS and UIPS, combined
with the IDP-like structure of many neurodegenerative disease-associated proteins,
might contribute. Strikingly, the 20S has been shown to predominate in older neurons
and to preferentially act on relevant substrates, such as synuclein and tau. Moreover,
pharmacological activation of the 20S has been shown to accelerate removal of aggregation-prone
proteins in some models. Together, these recent studies are turning attention to the
20S and the UIPS as potential therapeutic targets in neurodegeneration.
Abbreviations:
20S (core 20S proteasome), AD (Alzheimer's disease), ALS (amyotrophic lateral sclerosis), ATP (adenosine triphosphate), BBB (blood-brain barrier), DUB (deubiquitinating enzyme), HbYX (hydrophobic-tyrosine-unspecified residue ‘X’), IDP (intrinsically disordered protein), IDR (intrinsically-disordered region), LLVY-amc (succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin), NCC (NIH (National Institute of Health) clinical collection), NPL (Natural Product Library), PA (proteasome activators), PAINS (pan-assay interference compounds), PD (Parkinson's disease), ROS (reactive oxygen species), Rpt (regulatory particle of triple-ATPase), SAR (structure-activity relationship), tau (microtubule-associated protein tau (MAPT)), TDP-43 (trans-activation response element (TAR) DNA-binding protein 43), Ub (ubiquitin), UIPS (ubiquitin-independent proteasome system), UPS (ubiquitin-proteasome system), USP-14 (ubiquitin-specific-processing protease)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: June 18, 2018
Accepted:
May 15,
2018
Received in revised form:
May 14,
2018
Received:
April 8,
2018
Identification
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