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However, the molecular mechanism for this distinct vulnerability remains unclear. Here, it is shown that Legumain, also known as asparagine endopeptidase (AEP), is activated in a subgroup of SRY\u2010box transcription factor 6 \/Aldehyde dehydrogenase 1 family member A1, (Sox6<jats:sup>+<\/jats:sup>\/ALDH1A1<jats:sup>+<\/jats:sup>) neurons in the ventral tier of the SNpc and cleaves Sox6 and ALDH1A1, leading to repression of Special AT\u2010rich sequence binding protein 1 (Satb1) that is a dimeric\/tetrameric transcription factor specifically binding to AT\u2010rich DNA sequences, and toxic dopamine metabolite accumulation. AEP cuts Sox6 and ALDH1A1 in dopaminergic neurons that project to the locus coeruleus (LC), abolishing Sox6's transcriptive and ALDH1A1's enzymatic activities. Co\u2010expressing AEP\u2010truncated Sox6 and ALDH1A1 fragments in 3\u2010month\u2010old A53T SNCA transgenic mice accelerates dopamine degeneration, whereas expressing AEP\u2010resistant Sox6 N336A\/N446A and ALDH1A1 N220A mutants alleviates rotenone\u2010induced PD pathologies. Hence, different circuitries and intrinsic properties of dopaminergic neurons in the SNpc and VTA render differential predispositions in PD.<\/jats:p>","DOI":"10.1002\/advs.202409477","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T02:33:46Z","timestamp":1732242826000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Sox6 and ALDH1A1 Truncation by Asparagine Endopeptidase Defines Selective Neuronal Vulnerability in Parkinson's Disease"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3776-2749","authenticated-orcid":false,"given":"Shuke","family":"Nie","sequence":"first","affiliation":[{"name":"Department of Neurology Renmin Hospital of Wuhan University  Wuhan Hubei 430060 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowei","family":"Li","sequence":"additional","affiliation":[{"name":"Brain Cognition and Brain 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