{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:41:33Z","timestamp":1790847693482,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T00:00:00Z","timestamp":1624492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2020R1A6A1A03043708"],"award-info":[{"award-number":["NRF-2020R1A6A1A03043708"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2018R1DA1A02086100"],"award-info":[{"award-number":["NRF-2018R1DA1A02086100"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Neurodegenerative diseases, including Alzheimer\u2019s disease, Huntington\u2019s disease, and Parkinson\u2019s disease, are a class of diseases that lead to dysfunction of cognition and mobility. Aggregates of misfolded proteins such as \u03b2-amyloid, tau, \u03b1-synuclein, and polyglutamates are known to be among the main causes of neurodegenerative diseases; however, they are considered to be some of the most challenging drug targets because they cannot be modulated by conventional small-molecule agents. Recently, the degradation of target proteins by small molecules has emerged as a new therapeutic modality and has garnered the interest of the researchers in the pharmaceutical industry. Bifunctional molecules that recruit target proteins to a cellular protein degradation machinery, such as the ubiquitin\u2013proteasome system and autophagy\u2013lysosome pathway, have been designed. The representative targeted protein degradation technologies include molecular glues, proteolysis-targeting chimeras, hydrophobic tagging, autophagy-targeting chimeras, and autophagosome-tethering compounds. Although these modalities have been shown to degrade many disease-related proteins, such technologies are expected to be potentially important for neurogenerative diseases caused by protein aggregation. Herein, we review the recent progress in chemical-mediated targeted protein degradation toward the discovery of drugs for neurogenerative diseases.<\/jats:p>","DOI":"10.3390\/life11070607","type":"journal-article","created":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T11:01:38Z","timestamp":1624532498000},"page":"607","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3400-7353","authenticated-orcid":false,"given":"Soonsil","family":"Hyun","sequence":"first","affiliation":[{"name":"Gachon Institute of Pharmaceutical Science, College of Pharmacy, Gachon University, Yeonsu-gu, Incheon 21936, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyun","family":"Shin","sequence":"additional","affiliation":[{"name":"Gachon Institute of Pharmaceutical Science, College of Pharmacy, Gachon University, Yeonsu-gu, Incheon 21936, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1146\/annurev-biochem-061516-044518","article-title":"Protein Misfolding Diseases","volume":"86","author":"Hartl","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.conb.2018.04.027","article-title":"Tau-mediated synaptic and neuronal dysfunction in neurodegenerative disease","volume":"51","author":"Tracy","year":"2018","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"656","DOI":"10.2174\/156720510793611592","article-title":"Tau in Alzheimer Disease and Related Tauopathies","volume":"7","author":"Iqbal","year":"2010","journal-title":"Curr. Alzheimer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"809","DOI":"10.3389\/fneur.2018.00809","article-title":"Tau Pathology in Parkinson\u2019s Disease","volume":"9","author":"Zhang","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"259","DOI":"10.31887\/DCNS.2004.6.3\/galexander","article-title":"Biology of Parkinson\u2019s disease: Pathogenesis and pathophysiology of a multisystem neurodegenerative disorder","volume":"6","author":"Alexander","year":"2004","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"G\u00f3mez-Benito, M., Granado, N., Garc\u00eda-Sanz, P., Michel, A., Dumoulin, M., and Moratalla, R. (2020). Modeling Parkinson\u2019s Disease With the Alpha-Synuclein Protein. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.00356"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.ncl.2014.09.003","article-title":"Huntington disease: Pathogenesis and treatment","volume":"33","author":"Dayalu","year":"2015","journal-title":"Neurol. Clin."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5070","DOI":"10.1038\/s41598-017-05336-7","article-title":"Polyglutamine expansion affects huntingtin conformation in multiple Huntington\u2019s disease models","volume":"7","author":"Daldin","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"a024240","DOI":"10.1101\/cshperspect.a024240","article-title":"Huntington\u2019s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies","volume":"7","author":"Licitra","year":"2017","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.expneurol.2011.12.013","article-title":"Protein aggregates in Huntington\u2019s disease","volume":"238","author":"Arrasate","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"311","DOI":"10.3233\/JAD-2010-1221","article-title":"Alzheimer\u2019s Disease and the Amyloid-\u03b2 Peptide","volume":"19","author":"Murphy","year":"2010","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1146\/annurev-neuro-061010-113613","article-title":"Amyloid Precursor Protein Processing and Alzheimer\u2019s Disease","volume":"34","author":"Wong","year":"2011","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1126\/science.aax3769","article-title":"Cellular quality control by the ubiquitin-proteasome system and autophagy","volume":"366","author":"Pohl","year":"2019","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"835","DOI":"10.3389\/fphys.2019.00835","article-title":"Enzymatic Logic of Ubiquitin Chain Assembly","volume":"10","author":"Deol","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"R215","DOI":"10.1016\/j.cub.2014.02.002","article-title":"Ubiquitin code assembly and disassembly","volume":"24","author":"Heride","year":"2014","journal-title":"Curr. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/cr.2013.168","article-title":"The machinery of macroautophagy","volume":"24","author":"Feng","year":"2014","journal-title":"Cell Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/nrn2499","article-title":"Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction","volume":"9","author":"Tai","year":"2008","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.tins.2006.11.003","article-title":"Interplay between protein synthesis and degradation in the CNS: Physiological and pathological implications","volume":"30","author":"Ding","year":"2007","journal-title":"Trends Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Medina, M. (2018). An Overview on the Clinical Development of Tau-Based Therapeutics. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19041160"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/j.chembiol.2017.05.024","article-title":"Targeted Protein Degradation: From Chemical Biology to Drug Discovery","volume":"24","author":"Cromm","year":"2017","journal-title":"Cell Chem. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.cell.2020.12.020","article-title":"The Rise of Molecular Glues","volume":"184","author":"Schreiber","year":"2021","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.3389\/fphar.2021.692574","article-title":"PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy","volume":"12","author":"Qi","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.molcel.2019.09.009","article-title":"AUTACs: Cargo-Specific Degraders Using Selective Autophagy","volume":"76","author":"Takahashi","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/s41586-020-2545-9","article-title":"Lysosome-targeting chimaeras for degradation of extracellular proteins","volume":"584","author":"Banik","year":"2020","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.chembiol.2016.02.016","article-title":"Specific Knockdown of Endogenous Tau Protein by Peptide-Directed Ubiquitin-Proteasome Degradation","volume":"23","author":"Chu","year":"2016","journal-title":"Cell Chem. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"40362","DOI":"10.1039\/C7RA05347A","article-title":"Hydrophobic tagging-mediated degradation of Alzheimer\u2019s disease related Tau","volume":"7","author":"Gao","year":"2017","journal-title":"RSC Adv."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gao, N., Chen, Y.-X., Zhao, Y.-F., and Li, Y.-M. (2017). Chemical Methods to Knock Down the Amyloid Proteins. Molecules, 22.","DOI":"10.3390\/molecules22060916"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.ejmech.2018.01.063","article-title":"Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway","volume":"146","author":"Lu","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.tox.2007.10.029","article-title":"The Nrf2\u2013Keap1 defence pathway: Role in protection against drug-induced toxicity","volume":"246","author":"Copple","year":"2008","journal-title":"Toxicology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1021\/acsmedchemlett.9b00083","article-title":"Treatment of Alzheimer\u2019s by PROTAC-Tau Protein Degradation","volume":"10","author":"Kargbo","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_31","unstructured":"Gray, N.S., Haggarty, S.J., Cai, Q., Telo Baptista Lima Da Silva, M.C., Zhang, T., and Ferguson, F.M. (2019). Compounds for Tau Protein Degradation. (WO2019014429), U.S. Patent."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e45457","DOI":"10.7554\/eLife.45457","article-title":"Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models","volume":"8","author":"Silva","year":"2019","journal-title":"eLife"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11530","DOI":"10.1002\/anie.201706529","article-title":"Discovery of Small Molecules that Induce the Degradation of Huntingtin","volume":"56","author":"Tomoshige","year":"2017","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"115175","DOI":"10.1016\/j.bmc.2019.115175","article-title":"Application of protein knockdown strategy targeting \u03b2-sheet structure to multiple disease-associated polyglutamine proteins","volume":"28","author":"Yamashita","year":"2020","journal-title":"Bioorg. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.bmcl.2018.01.012","article-title":"Degradation of huntingtin mediated by a hybrid molecule composed of IAP antagonist linked to phenyldiazenyl benzothiazole derivative","volume":"28","author":"Tomoshige","year":"2018","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1080\/15548627.2019.1688556","article-title":"ATTEC: A potential new approach to target proteinopathies","volume":"16","author":"Li","year":"2020","journal-title":"Autophagy"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41586-019-1722-1","article-title":"Allele-selective lowering of mutant HTT protein by HTT\u2013LC3 linker compounds","volume":"575","author":"Li","year":"2019","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/nn.3637","article-title":"Rapid and reversible knockdown of endogenous proteins by peptide-directed lysosomal degradation","volume":"17","author":"Fan","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1021\/acsmedchemlett.0c00192","article-title":"PROTAC Compounds Targeting \u03b1-Synuclein Protein for Treating Neurogenerative Disorders: Alzheimer\u2019s and Parkinson\u2019s Diseases","volume":"11","author":"Kargbo","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.bioorg.2018.11.042","article-title":"TDP-43 specific reduction induced by Di-hydrophobic tags conjugated peptides","volume":"84","author":"Gao","year":"2019","journal-title":"Bioorg. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1126\/science.aam7340","article-title":"Waste disposal\u2014An attractive strategy for cancer therapy","volume":"355","author":"Salami","year":"2017","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/164_2017_60","article-title":"Targeting of Disordered Proteins by Small Molecules in Neurodegenerative Diseases","volume":"245","author":"Longhena","year":"2018","journal-title":"Handb. Exp. Pharmacol."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/11\/7\/607\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:22:47Z","timestamp":1760163767000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/11\/7\/607"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,24]]},"references-count":42,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["life11070607"],"URL":"https:\/\/doi.org\/10.3390\/life11070607","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,24]]}}}