The pivotal role of Ubiquitin-activating enzyme E1 (UBA1) in neuronal health and neurodegeneration

I couldn't make heads or tails out of this, enzymatic ubiquitylation cascade, so go ask your doctor. Should we initiate or suppress this and how do we do it? 

The pivotal role of Ubiquitin-activating enzyme E1 (UBA1) in neuronal health and neurodegeneration

Author links open overlay panelIsabella A.Lambert-Smith^abDarren N.Saunders^c

Justin J.Yerbury^ab

https://doi.org/10.1016/j.biocel.2020.105746Get rights and content

Highlights

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UBA1 is the ubiquitin activator and as such functions at the apex of the enzymatic ubiquitylation cascade.

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UBA1 activity is vital to many aspects of neural function, including growth and development, neuronal excitability, neurotransmission, and long-term potentiation.

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Alteration of UBA1 level, location or activity is associated with neurological disorders including mutations causing spinal muscular atrophy.

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UBA1 modulation may provide potential therapeutic targets for neurological disorders.

Abstract

Ubiquitin-activating enzyme E1, UBA1, functions at the apex of the enzymatic ubiquitylation cascade, catalysing ubiquitin activation. UBA1 is thus of fundamental importance to the modulation of ubiquitin homeostasis and to all downstream ubiquitylation-dependent cellular processes, including proteolysis through the ubiquitin-proteasome system and selective autophagy. The proteasome-dependent and -independent functions of UBA1 contribute significantly to a range of processes crucial to neuronal health. The significance of UBA1 activity to neuronal health is clear in light of accumulating evidence implicating impaired UBA1 activity in a range of neurodegenerative conditions, including Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and spinal muscular atrophy. Moreover, ubiquitylation-independent functions of UBA1 of importance to neuronal functioning have been proposed. Here, we summarise findings supporting the significant role of UBA1 in regulating neuronal functioning, and discuss the detrimental consequences of UBA1 impairment that contribute to neuronal dysfunction and degeneration.