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The deposition of abnormal protein aggregates in the brain of patients affected by these disorders is thought to play a causative role in neuronal loss and disease progression. On that account, the idea of improving the clearance of pathological protein aggregates has taken hold as a potential therapeutic strategy. Among the possible approaches to pursue for reducing disease protein accumulation, there is the stimulation of the main protein degradation machineries of eukaryotic cells: the ubiquitin proteasomal system (UPS) and autophagy lysosomal pathway (ALP). Of note, several clinical trials testing the efficacy of either UPS\u2010 or ALP\u2010active compounds are currently ongoing. Here, we discuss the main gaps and controversies emerging from experimental studies and clinical trials assessing the therapeutic efficacy of modulators of either the UPS or ALP in neurodegenerative proteinopathies, to gather whether they may constitute a real gateway from these disorders. \u00a9 2022 International Parkinson and Movement Disorder Society.<\/jats:p>","DOI":"10.1002\/mds.29058","type":"journal-article","created":{"date-parts":[[2022,5,17]],"date-time":"2022-05-17T08:58:08Z","timestamp":1652777888000},"page":"1346-1359","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Can We Treat Neurodegenerative Proteinopathies by Enhancing Protein Degradation?"],"prefix":"10.1002","volume":"37","author":[{"given":"Simone","family":"Engelender","sequence":"first","affiliation":[{"name":"Department of Biochemistry, The B. Rappaport Faculty of Medicine and Institute of Medical Research Technion\u2010Israel Institute of Technology  Haifa Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonidas","family":"Stefanis","sequence":"additional","affiliation":[{"name":"Biomedical Research Foundation of the Academy of Athens  Athens Greece"},{"name":"First Department of Neurology National and Kapodistrian University of Athens Medical School  Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Oddo","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences University of Messina  Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9581-1919","authenticated-orcid":false,"given":"Arianna","family":"Bellucci","sequence":"additional","affiliation":[{"name":"Department of Molecular and Translational Medicine University of 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