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Sox6 and ALDH1A1 Truncation by Asparagine Endopeptidase Defines Selective Neuronal Vulnerability in Parkinson's Disease
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Sox6 and ALDH1A1 Truncation by Asparagine Endopeptidase Defines Selective Neuronal Vulnerability in Parkinson's Disease
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Journal Article
Sox6 and ALDH1A1 Truncation by Asparagine Endopeptidase Defines Selective Neuronal Vulnerability in Parkinson's Disease
2025
Overview
Dopaminergic neurons in the substantia nigra pars compacta (SNpc) demonstrate regionally selective susceptibility in Parkinson's disease (PD) compared to those in the ventral tegmental area (VTA). 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‐box transcription factor 6 /Aldehyde dehydrogenase 1 family member A1, (Sox6+/ALDH1A1+) neurons in the ventral tier of the SNpc and cleaves Sox6 and ALDH1A1, leading to repression of Special AT‐rich sequence binding protein 1 (Satb1) that is a dimeric/tetrameric transcription factor specifically binding to AT‐rich 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‐expressing AEP‐truncated Sox6 and ALDH1A1 fragments in 3‐month‐old A53T SNCA transgenic mice accelerates dopamine degeneration, whereas expressing AEP‐resistant Sox6 N336A/N446A and ALDH1A1 N220A mutants alleviates rotenone‐induced PD pathologies. Hence, different circuitries and intrinsic properties of dopaminergic neurons in the SNpc and VTA render differential predispositions in PD. The Gut‐to‐brain propagation of pathologic α‐Syn via vagus nerve‐DMVN‐LC‐SN initiates PD. SNpc DA neurons form stronger connections with the LC than the VTA. AEP is subsequently activated by α‐Syn fibrils in the SNpc, leading to cleavage of Sox6 and ALDH1A1 in SNpc DA neurons, contributing to the vulnerability of dopaminergic neurons in Parkinson's disease.
Publisher
John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
Subject
Aldehyde Dehydrogenase - genetics
/ Aldehyde Dehydrogenase - metabolism
/ Aldehyde Dehydrogenase 1 Family - genetics
/ Aldehyde Dehydrogenase 1 Family - metabolism
/ ALDH1A1
/ Animals
/ Brain
/ Dopamine
/ Dopaminergic Neurons - metabolism
/ Dopaminergic Neurons - pathology
/ Humans
/ Male
/ Mice
/ Neurons
/ Parkinson Disease - genetics
/ Parkinson Disease - metabolism
/ Parkinson Disease - pathology
/ Patients
/ Retinal Dehydrogenase - genetics
/ Retinal Dehydrogenase - metabolism
/ Sox6
/ SOXD Transcription Factors - genetics
