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, 3350]

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 [5768]

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[6971]

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.