The Role of Deubiquitinating Enzymes in Synaptic Function and Nervous System Diseases

Table 1

Summary of DUBs at the synapse.

DUB	Neuronal localization and function	References
UCH family DUBs
UCH-L1/Ap-Uch	Localizes to dendritic spines and PSD in hippocampal neurons; maintains cellular levels of free ubiquitin by deubiquitinating precursor molecules and stabilizing monomeric ubiquitin; exhibits ubiquitin ligase activity as a dimer; required for normal synaptic structure and function; required for synaptic plasticity in Aplysia and mice; implicated in synaptic transmission defects in several neurodegenerative disorders including PD, AD, and gad	[26, 33–50]
UCH-L3/Ap-Uch	Required for long-term facilitation in Aplysia and working memory in mice	[26, 51]
UCH-L5/UCH37	Associated with the 26S proteasome at synapses; detected in PSDs of; hippocampal neurons	[47, 52]
USP family DUBs
USP4	Binds and deubiquitinates adenosine A2 receptors to prevent their degradation via ER-associated degradation and promotes their surface expression	[53]
USP5	Associated with the 26S proteasome at synapses	[52]
USP7	Associated with the 26S proteasome at synapses	[52]
USP8/UBPY	Highly expressed in brain; colocalizes with presynaptic markers	[54]
USP9x/Fat facets	Deubiquitinates the endocytic protein epsin in Drosophila and mammals; regulates presynaptic development and function in Drosophila	[27, 55, 56]
USP13	Associated with the 26S proteasome at synapses	[52]
USP14	Localized both pre- and postsynaptically; associated with the 19S regulatory particle of the proteasome; inhibits proteasome-mediated degradation of substrates by trimming ubiquitin chains and maintains cellular levels of free ubiquitin; loss of function mutations in mice result in defects in synapse development at the NMJ, and defects in synaptic transmission at both central and peripheral synapses, as well as ataxia; negatively regulates surface levels of GABA receptors in Purkinje neurons	[57–68]
USP46	Binds and deubiquitinates GLR-1 glutamate receptors to prevent their degradation in the MVB/lysosome pathway in C. elegans; Promotes GABA-dependent behaviors in mice	[69–71]
USP48/synUSP	Expressed in dendrites in cortical and hippocampal neurons; Enriched in PSDs and lipid rafts	[72]

Abbreviations: PD: Parkinson’s Disease; AD: Alzheimer’s Disease; gad: gracile axonal dystrophy; PSD: postsynaptic density.