Cellular functions regulated by deubiquitinating enzymes in neurodegenerative diseases

Alexopoulou, 2016, Deubiquitinase USP8 regulates alpha-synuclein clearance and modifies its toxicity in Lewy body disease, Proc. Natl. Acad. Sci. U. S. A., 113, E4688, 10.1073/pnas.1523597113 Altun, 2011, Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes, Chem. Biol., 18, 1401, 10.1016/j.chembiol.2011.08.018 Alwan, 2007, UBPY-mediated epidermal growth factor receptor (EGFR) de-ubiquitination promotes EGFR degradation, J. Biol. Chem., 282, 1658, 10.1074/jbc.M604711200 Amer-Sarsour, 2021, Deubiquitylating enzymes in neuronal health and disease, Cell Death Dis., 12, 120, 10.1038/s41419-020-03361-5 Aron, 2018, Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington’s disease, Nat. Commun., 9, 3191, 10.1038/s41467-018-05653-z Banerjee, 2020, USP14 as a therapeutic target against neurodegeneration: a rat brain perspective, Front. Cell Dev. Biol., 8, 727, 10.3389/fcell.2020.00727 Barman, 2020, CRISPR-Cas9: a promising genome editing therapeutic tool for Alzheimer’s disease-a narrative review, Neurol. Ther., 9, 419, 10.1007/s40120-020-00218-z Bates, 2015, Huntington disease, Nat. Rev. Dis. Primers, 1, 15005, 10.1038/nrdp.2015.5 Bettencourt, 2011, Machado-Joseph Disease: from first descriptions to new perspectives, Orphanet J. Rare Dis., 6, 35, 10.1186/1750-1172-6-35 Blokhuis, 2013, Protein aggregation in amyotrophic lateral sclerosis, Acta Neuropathol., 125, 777, 10.1007/s00401-013-1125-6 Blount, 2012, Ubiquitin-specific protease 25 functions in Endoplasmic Reticulum-associated degradation, PLoS One, 7, 10.1371/journal.pone.0036542 Burns, 2009, Alzheimer’s disease, BMJ, 338, b158, 10.1136/bmj.b158 Butti, 2018, RNA dysregulation in amyotrophic lateral sclerosis, Front. Genet., 9, 712, 10.3389/fgene.2018.00712 Canerina-Amaro, 2019, Differential aggregation and phosphorylation of alpha synuclein in membrane compartments associated with parkinson disease, Front. Neurosci., 13, 382, 10.3389/fnins.2019.00382 Carmine Belin, 2007, S18Y in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) associated with decreased risk of Parkinson’s disease in Sweden, Parkinsonism Relat. Disord., 13, 295, 10.1016/j.parkreldis.2006.12.002 Castillo, 2019, Re-thinking the etiological framework of neurodegeneration, Front. Neurosci., 13, 728, 10.3389/fnins.2019.00728 Celebi, 2020, The effect of dysfunctional ubiquitin enzymes in the pathogenesis of most common diseases, Int. J. Mol. Sci., 21, 6335, 10.3390/ijms21176335 Charbonneau, 2014, Small molecule deubiquitinase inhibitors promote macrophage anti-infective capacity, PLoS One, 9, e104096, 10.1371/journal.pone.0104096 Chauhan, 2012, A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance, Cancer Cell, 22, 345, 10.1016/j.ccr.2012.08.007 Chen, 2019, Ubiquitin-mediated regulation of autophagy, J. Biomed. Sci., 26, 80, 10.1186/s12929-019-0569-y Choi, 2004, Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson’s and Alzheimer’s diseases, J. Biol. Chem., 279, 13256, 10.1074/jbc.M314124200 Chung, 2001, Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease, Nat. Med., 7, 1144, 10.1038/nm1001-1144 Chung, 2018, Mechanisms of protein toxicity in neurodegenerative diseases, Cell. Mol. Life Sci., 75, 3159, 10.1007/s00018-018-2854-4 Ciechanover, 2003, The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg, Neuron, 40, 427, 10.1016/S0896-6273(03)00606-8 Ciechanover, 2015, Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies, Exp. Mol. Med., 47, e147, 10.1038/emm.2014.117 Clague, 2019, Breaking the chains: deubiquitylating enzyme specificity begets function, Nat. Rev. Mol. Cell Biol., 20, 338, 10.1038/s41580-019-0099-1 Colland, 2009, Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells, Mol. Cancer Ther., 8, 2286, 10.1158/1535-7163.MCT-09-0097 Colombo, 2010, Synthesis and biological evaluation of 9-oxo9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile analogues as potential inhibitors of deubiquitinating enzymes, ChemMedChem, 5, 552, 10.1002/cmdc.200900409 Cornelissen, 2014, The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy, Hum. Mol. Genet., 23, 5227, 10.1093/hmg/ddu244 Corti, 2011, What genetics tells us about the causes and mechanisms of Parkinson’s disease, Physiol. Rev., 91, 1161, 10.1152/physrev.00022.2010 Cunningham, 2015, USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria, Nat. Cell Biol., 17, 160, 10.1038/ncb3097 D’Arcy, 2011, Inhibition of proteasome deubiquitinating activity as a new cancer therapy, Nat. Med., 17, 1636, 10.1038/nm.2536 Dantuma, 2014, The ubiquitin-proteasome system in neurodegenerative diseases: precipitating factor, yet part of the solution, Front. Mol. Neurosci., 7, 70, 10.3389/fnmol.2014.00070 Das, 2020, Critical roles of deubiquitinating enzymes in the nervous system and neurodegenerative disorders, Mol. Cells, 43, 203 Davies, 2012, The co-crystal structure of ubiquitin carboxyterminal hydrolase L1 (UCHL1) with a tripeptide fluoromethyl ketone (Z-VAE(OMe)-FMK), Bioorg. Med. Chem. Lett., 22, 3900, 10.1016/j.bmcl.2012.04.124 Dawson, 2010, The role of parkin in familial and sporadic Parkinson’s disease, Mov. Disord., 25, S32, 10.1002/mds.22798 Duan, 2015, The roles of post-translational modifications in the context of protein interaction networks, PLoS Comput. Biol., 11, 10.1371/journal.pcbi.1004049 Durcan, 2011, Mutant ataxin-3 promotes the autophagic degradation of parkin, Autophagy, 7, 233, 10.4161/auto.7.2.14224 Durcan, 2012, Ataxin-3 deubiquitination is coupled to Parkin ubiquitination via E2 ubiquitin-conjugating enzyme, J. Biol. Chem., 287, 531, 10.1074/jbc.M111.288449 Durcan, 2014, USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin, EMBO J., 33, 2473, 10.15252/embj.201489729 Eliona Tsefou, 2021, Investigation of USP30 inhibition to enhance Parkin-mediated mitophagy: tools and approaches, bioRxiv, 429344 Fan, 2013, USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis, Cell Death Dis., 4, e867, 10.1038/cddis.2013.400 Frank, 2014, Treatment of Huntington’s disease, Neurotherapeutics, 11, 153, 10.1007/s13311-013-0244-z Gammon, 2014, Neurodegenerative disease: brain windfall, Nature, 515, 299, 10.1038/nj7526-299a Gao, 2008, Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression, Trends Immunol., 29, 357, 10.1016/j.it.2008.05.002 Gavory, 2018, Discovery and characterization of highly potent and selective allosteric USP7 inhibitors, Nat. Chem. Biol., 14, 118, 10.1038/nchembio.2528 Geisler, 2019, Ubiquitin-specific protease USP36 knockdown impairs Parkin-dependent mitophagy via downregulation of Beclin-1-associated autophagy-related ATG14L, Exp. Cell Res., 384, 10.1016/j.yexcr.2019.111641 Goate, 2012, Twenty years of Alzheimer’s disease-causing mutations, J. Neurochem., 120, 3, 10.1111/j.1471-4159.2011.07575.x Gomez-Benito, 2020, Modeling Parkinson’s Disease with the alpha-synuclein protein, Front. Pharmacol., 11, 356, 10.3389/fphar.2020.00356 Gong, 2006, Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory, Cell, 126, 775, 10.1016/j.cell.2006.06.046 Goto, 2009, Proteomic and histochemical analysis of proteins involved in the dying-back-type of axonal degeneration in the gracile axonal dystrophy (gad) mouse, Neurochem. Int., 54, 330, 10.1016/j.neuint.2008.12.012 Grima, 2017, Mutant huntingtin disrupts the nuclear pore complex, Neuron, 94, e106 Gusella, 2000, Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease, Nat. Rev. Neurosci., 1, 109, 10.1038/35039051 Hanna, 2019, Protein degradation and the pathologic basis of disease, Am. J. Pathol., 189, 94, 10.1016/j.ajpath.2018.09.004 Hans, 2014, UBE2E ubiquitin-conjugating enzymes and ubiquitin isopeptidase Y regulate TDP-43 protein ubiquitination, J. Biol. Chem., 289, 19164, 10.1074/jbc.M114.561704 Hara, 2006, Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice, Nature, 441, 885, 10.1038/nature04724 He, 2016, The emerging role of deubiquitinating enzymes in genomic integrity, diseases, and therapeutics, Cell Biosci., 6, 62, 10.1186/s13578-016-0127-1 He, 2017, HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19, Sci. Rep., 7, 14797, 10.1038/s41598-017-13711-7 Hohn, 2017, Happily (n)ever after: aging in the context of oxidative stress, proteostasis loss and cellular senescence, Redox Biol., 11, 482, 10.1016/j.redox.2016.12.001 Hua, 2010, Sex and age differences in atrophic rates: an ADNI study with n=1368 MRI scans, Neurobiol. Aging, 31, 1463, 10.1016/j.neurobiolaging.2010.04.033 Hurst-Kennedy, 2012, Ubiquitin C-terminal hydrolase l1 in tumorigenesis, Biochem. Res. Int., 2012, 123706, 10.1155/2012/123706 Hussain, 2018, Neurodegenerative diseases: regenerative mechanisms and novel therapeutic approaches, Brain Sci., 8, 177, 10.3390/brainsci8090177 Hyrskyluoto, 2014, Ubiquitin-specific protease-14 reduces cellular aggregates and protects against mutant huntingtin-induced cell degeneration: involvement of the proteasome and ER stress-activated kinase IRE1alpha, Hum. Mol. Genet., 23, 5928, 10.1093/hmg/ddu317 Issaenko, 2012, Chalcone-based small-molecule inhibitors attenuate malignant phenotype via targeting deubiquitinating enzymes, Cell Cycle, 11, 1804, 10.4161/cc.20174 Jiang, 2016, Oxidative stress: a major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson’s disease and Alzheimer’s disease, Prog. Neurobiol., 147, 1, 10.1016/j.pneurobio.2016.07.005 Jung, 2015, Acute ER stress regulates amyloid precursor protein processing through ubiquitin-dependent degradation, Sci. Rep., 5, 8805, 10.1038/srep08805 Kalia, 2015, Parkinson’s disease, Lancet, 386, 896, 10.1016/S0140-6736(14)61393-3 Kapuria, 2010, Deubiquitinase inhibition by small-molecule WP1130 triggers aggresome formation and tumor cell apoptosis, Cancer Res., 70, 9265, 10.1158/0008-5472.CAN-10-1530 Kategaya, 2017, USP7 small-molecule inhibitors interfere with ubiquitin binding, Nature, 550, 534, 10.1038/nature24006 Kato, 2000, A deubiquitinating enzyme UBPY interacts with the Src homology 3 domain of Hrs-binding protein via a novel binding motif PX(V/I)(D/N)RXXKP, J. Biol. Chem., 275, 37481, 10.1074/jbc.M007251200 Kim, 2010, Nedd4‐2 ubiquitin ligase interacts with RCAN1 (DSCR1) for the proteasomal degradation, Genes Genomics, 32, 582, 10.1007/s13258-010-0109-3 Kim, 2020, ALS genetics: gains, losses, and implications for future therapies, Neuron, 108, 822, 10.1016/j.neuron.2020.08.022 Kiprowska, 2017, Neurotoxic mechanisms by which the USP14 inhibitor IU1 depletes ubiquitinated proteins and Tau in rat cerebral cortical neurons: relevance to Alzheimer’s disease, Biochim Biophys Acta Mol Basis Dis, 1863, 1157, 10.1016/j.bbadis.2017.03.017 Kluge, 2018, Novel highly selective inhibitors of ubiquitin specific protease 30 (USP30) accelerate mitophagy, Bioorg. Med. Chem. Lett., 28, 2655, 10.1016/j.bmcl.2018.05.013 Ko, 2008, Aggregates assembled from overexpression of wild-type alpha-synuclein are not toxic to human neuronal cells, J. Neuropathol. Exp. Neurol., 67, 1084, 10.1097/NEN.0b013e31818c3618 Koglsberger, 2017, Gender-specific expression of ubiquitin-specific peptidase 9 modulates Tau expression and phosphorylation: possible implications for tauopathies, Mol. Neurobiol., 54, 7979, 10.1007/s12035-016-0299-z Koh, 2005, BACE is degraded via the lysosomal pathway, J. Biol. Chem., 280, 32499, 10.1074/jbc.M506199200 Komander, 2012, The ubiquitin code, Annu. Rev. Biochem., 81, 203, 10.1146/annurev-biochem-060310-170328 Kumari, 2020, Amyloid aggregates of the deubiquitinase OTUB1 are neurotoxic, suggesting that they contribute to the development of Parkinson's disease, J. Biol. Chem., 295, 3466, 10.1074/jbc.RA119.009546 Kwon, 2017, p53 stability is regulated by diverse deubiquitinating enzymes, Biochim. Biophys. Acta Rev. Cancer, 1868, 404, 10.1016/j.bbcan.2017.08.001 Lahue, 2020, New developments in Huntington’s disease and other triplet repeat diseases: DNA repair turns to the dark side, Neuronal Signal, 4, NS20200010, 10.1042/NS20200010 Lamberto, 2017, Structure-guided development of a potent and selective non-covalent active-site inhibitor of USP7, Cell Chem. Biol., 24, 1490, 10.1016/j.chembiol.2017.09.003 Landles, 2010, Proteolysis of mutant huntingtin produces an exon 1 fragment that accumulates as an aggregated protein in neuronal nuclei in Huntington disease, J. Biol. Chem., 285, 8808, 10.1074/jbc.M109.075028 Lashuel, 2013, The many faces of alpha-synuclein: from structure and toxicity to therapeutic target, Nat. Rev. Neurosci., 14, 38, 10.1038/nrn3406 Le Guerroue, 2021, Ubiquitin signaling in neurodegenerative diseases: an autophagy and proteasome perspective, Cell Death Differ., 28, 439, 10.1038/s41418-020-00667-x Lee, 2010, Enhancement of proteasome activity by a small-molecule inhibitor of USP14, Nature, 467, 179, 10.1038/nature09299 Lee, 2015, Facilitated tau degradation by USP14 aptamers via enhanced proteasome activity, Sci. Rep., 5, 10757, 10.1038/srep10757 Leroy, 1998, The ubiquitin pathway in Parkinson’s disease, Nature, 395, 451, 10.1038/26652 Liang, 2015, USP30 deubiquitylates mitochondrial Parkin substrates and restricts apoptotic cell death, EMBO Rep., 16, 618, 10.15252/embr.201439820 Lim, 2013, Molecular mechanisms and functions of cytokine-inducible deubiquitinating enzymes, Cytokine Growth Factor Rev., 24, 427, 10.1016/j.cytogfr.2013.05.007 Liu, 2021, Regulatory role of ubiquitin specific protease-13 (USP13) in misfolded protein clearance in neurodegenerative diseases, Neuroscience, 460, 161, 10.1016/j.neuroscience.2021.02.004 Liu, 2002, The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson’s disease susceptibility, Cell, 111, 209, 10.1016/S0092-8674(02)01012-7 Liu, 2014, Clinically used antirheumatic agent auranofin is a proteasomal deubiquitinase inhibitor and inhibits tumor growth, Oncotarget, 5, 5453, 10.18632/oncotarget.2113 Liu, 2019, Ubiquitin specific protease-13 independently regulates parkin ubiquitination and alpha-synuclein clearance in alpha-synucleinopathies, Hum. Mol. Genet., 28, 548, 10.1093/hmg/ddy365 Liu, 2019, Ubiquitin specific protease 13 regulates Tau accumulation and clearance in models of Alzheimer’s disease, J. Alzheimers Dis., 72, 425, 10.3233/JAD-190635 Liu, 2011, Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13, Cell, 147, 223, 10.1016/j.cell.2011.08.037 Lonskaya, 2013, Decreased parkin solubility is associated with impairment of autophagy in the nigrostriatum of sporadic Parkinson’s disease, Neuroscience, 232, 90, 10.1016/j.neuroscience.2012.12.018 Lonskaya, 2013, Tyrosine kinase inhibition increases functional parkin-Beclin-1 interaction and enhances amyloid clearance and cognitive performance, EMBO Mol. Med., 5, 1247, 10.1002/emmm.201302771 Lonskaya, 2015, Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer’s disease models, Neuroscience, 304, 316, 10.1016/j.neuroscience.2015.07.070 Majd, 2015, Neuronal response in Alzheimer’s and Parkinson’s disease: the effect of toxic proteins on intracellular pathways, BMC Neurosci., 16, 69, 10.1186/s12868-015-0211-1 McKinnon, 2014, The ubiquitin-proteasome system in neurodegeneration, Antioxid. Redox Signal., 21, 2302, 10.1089/ars.2013.5802 Mermerian, 2007, Structureactivity relationship, kinetic mechanism, and selectivity for a new class of ubiquitin C-terminal hydrolase-L1 (UCH-L1) inhibitors, Bioorg. Med. Chem. Lett., 17, 3729, 10.1016/j.bmcl.2007.04.027 Narendra, 2008, Parkin is recruited selectively to impaired mitochondria and promotes their autophagy, J. Cell Biol., 183, 795, 10.1083/jcb.200809125 Neddens, 2018, Phosphorylation of different tau sites during progression of Alzheimer’s disease, Acta Neuropathol. Commun., 6, 52, 10.1186/s40478-018-0557-6 Neueder, 2017, The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients, Sci. Rep., 7, 1307, 10.1038/s41598-017-01510-z Nicholson, 2008, Characterization of ubiquitin and ubiquitin-like-protein isopeptidase activities, Protein Sci., 17, 1035, 10.1110/ps.083450408 Niu, 2020, USP33 deubiquitinates PRKN/parkin and antagonizes its role in mitophagy, Autophagy, 16, 724, 10.1080/15548627.2019.1656957 Okada, 2013, Vialinin A is a ubiquitin-specific peptidase inhibitor, Bioorg. Med. Chem. Lett., 23, 4328, 10.1016/j.bmcl.2013.05.093 Ortuno, 2016, Does inactivation of USP14 enhance degradation of proteasomal substrates that are associated with neurodegenerative diseases?, F1000Res, 5, 137, 10.12688/f1000research.7800.1 Panicker, 2017, Activation mechanisms of the E3 ubiquitin ligase parkin, Biochem. J., 474, 3075, 10.1042/BCJ20170476 Pickart, 2004, Ubiquitin: structures, functions, mechanisms, Biochim. Biophys. Acta, 1695, 55, 10.1016/j.bbamcr.2004.09.019 Rajmohan, 2017, Amyloid-beta and phosphorylated tau accumulations cause abnormalities at synapses of Alzheimer’s disease neurons, J. Alzheimers Dis., 57, 975, 10.3233/JAD-160612 Reverdy, 2012, Discovery of specific inhibitors of human USP7/HAUSP deubiquitinating enzyme, Chem. Biol., 19, 467, 10.1016/j.chembiol.2012.02.007 Reyes-Turcu, 2009, Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes, Annu. Rev. Biochem., 78, 363, 10.1146/annurev.biochem.78.082307.091526 Ross, 2011, Huntington’s disease: from molecular pathogenesis to clinical treatment, Lancet Neurol., 10, 83, 10.1016/S1474-4422(10)70245-3 Rott, 2011, Alpha-Synuclein fate is determined by USP9X-regulated monoubiquitination, Proc. Natl. Acad. Sci. U. S. A., 108, 18666, 10.1073/pnas.1105725108 Rusilowicz-Jones, 2020, USP30 sets a trigger threshold for PINK1-PARKIN amplification of mitochondrial ubiquitylation, Life Sci Alliance, 3, 10.26508/lsa.202000768 Ruz, 2020, Proteotoxicity and neurodegenerative diseases, Int. J. Mol. Sci., 21, 5646, 10.3390/ijms21165646 Sarraf, 2013, Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization, Nature, 496, 372, 10.1038/nature12043 Schaffert, 2020, Do post-translational modifications influence protein aggregation in neurodegenerative diseases: a systematic review, Brain Sci., 10, 232, 10.3390/brainsci10040232 Schmidt, 2021, Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities, Cell Death Differ., 28, 570, 10.1038/s41418-020-00706-7 Seiberlich, 2012, The small molecule inhibitor PR-619 of deubiquitinating enzymes affects the microtubule network and causes protein aggregate formation in neural cells: implications for neurodegenerative diseases, Biochim. Biophys. Acta, 1823, 2057, 10.1016/j.bbamcr.2012.04.011 Seyfried, 2017, A multi-network approach identifies protein-specific Co-expression in asymptomatic and symptomatic alzheimer’s disease, Cell Syst., 4, e64 Sweeney, 2017, Protein misfolding in neurodegenerative diseases: implications and strategies, Transl. Neurodegener., 6, 6, 10.1186/s40035-017-0077-5 Taillebourg, 2012, The deubiquitinating enzyme USP36 controls selective autophagy activation by ubiquitinated proteins, Autophagy, 8, 767, 10.4161/auto.19381 Takiyama, 1993, The gene for Machado-Joseph disease maps to human chromosome 14q, Nat. Genet., 4, 300, 10.1038/ng0793-300 Thayer, 2020, The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability, Autophagy, 16, 140, 10.1080/15548627.2019.1598754 Turnbull, 2017, Molecular basis of USP7 inhibition by selective small-molecule inhibitors, Nature, 7677, 481, 10.1038/nature24451 Vassar, 1999, Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE, Science, 286, 735, 10.1126/science.286.5440.735 Vives-Bauza, 2010, PINK1-dependent recruitment of Parkin to mitochondria in mitophagy, Proc. Natl. Acad. Sci. U. S. A., 107, 378, 10.1073/pnas.0911187107 von Stockum, 2019, Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction, Life Sci Alliance, 2, e201900392, 10.26508/lsa.201900392 Wang, 2008, Inhibition of p97-dependent protein degradation by Eeyarestatin I. J, Biol. Chem., 283, 7445, 10.1074/jbc.M708347200 Wang, 2015, Deubiquitinating enzymes regulate PARK2-mediated mitophagy, Autophagy, 11, 595, 10.1080/15548627.2015.1034408 Wang, 2016, The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitinspecific protease-14 and induces apoptosis of multiple myeloma cells, Sci. Rep., 6, 26979, 10.1038/srep26979 Wang, 2017, Tau interactome mapping based identification of Otub1 as Tau deubiquitinase involved in accumulation of pathological Tau forms in vitro and in vivo, Acta Neuropathol., 133, 731, 10.1007/s00401-016-1663-9 Wang, 2018, Small molecule inhibitors reveal allosteric regulation of USP14 via steric blockade, Cell Res., 28, 1186, 10.1038/s41422-018-0091-x Ward, 2016, Quantitative chemical proteomic profiling of ubiquitin specific proteases in intact cancer cells, ACS Chem. Biol., 11, 3268, 10.1021/acschembio.6b00766 Weinstock, 2012, Selective dual inhibitors of the cancer-related deubiquitylating proteases USP7 and USP47, ACS Med. Chem. Lett., 3, 789, 10.1021/ml200276j Wenya Yang, 2020, Current and projected future economic burden of Parkinson’s disease in the U.S, NPJ Parkinsons Dis., 6, 15, 10.1038/s41531-020-0117-1 Woerner, 2016, Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA, Science, 351, 173, 10.1126/science.aad2033 Wrigley, 2017, Identification and characterization of dual inhibitors of the USP25/28 deubiquitinating enzyme subfamily, ACS Chem. Biol., 12, 3113, 10.1021/acschembio.7b00334 Yamaguchi, 2013, A pyrrole alkaloid from the marine sponge Stylissa massa, functions as a USP7 inhibitor, Bioorg. Med. Chem. Lett., 23, 3884, 10.1016/j.bmcl.2013.04.066 Yamazaki, 1988, Gracile axonal dystrophy (GAD), a new neurological mutant in the mouse, Proc. Soc. Exp. Biol. Med., 187, 209, 10.3181/00379727-187-42656 Yeates, 2016, The endosome-associated deubiquitinating enzyme USP8 regulates BACE1 enzyme ubiquitination and degradation, J. Biol. Chem., 291, 15753, 10.1074/jbc.M116.718023 Yue, 2014, A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30, Cell Res., 24, 482, 10.1038/cr.2014.20 Zhang, 2014, Overexpression of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) delays Alzheimer's progression in vivo, Sci. Rep., 4, 7298, 10.1038/srep07298 Zhang, 2015, Parkin regulation and neurodegenerative disorders, Front. Aging Neurosci., 7, 248 Zhang, 2020, USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L-SMAD pathway, Proc. Natl. Acad. Sci. U. S. A., 117, 28114, 10.1073/pnas.2014349117 Zuccato, 2010, Molecular mechanisms and potential therapeutical targets in Huntington’s disease, Physiol. Rev., 90, 905, 10.1152/physrev.00041.2009