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Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models

2022-04-28Artigo científico Acesso aberto
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dc.contributor.authorPrieto Huarcaya, Susy
dc.contributor.authorDrobny, Alice
dc.contributor.authorMarques, André R A
dc.contributor.authorDi Spiezio, Alessandro
dc.contributor.authorDobert, Jan Philipp
dc.contributor.authorBalta, Denise
dc.contributor.authorWerner, Christian
dc.contributor.authorRizo, Tania
dc.contributor.authorGallwitz, Lisa
dc.contributor.authorBub, Simon
dc.contributor.authorStojkovska, Iva
dc.contributor.authorBelur, Nandkishore R
dc.contributor.authorFogh, Jens
dc.contributor.authorMazzulli, Joseph R
dc.contributor.authorXiang, Wei
dc.contributor.authorFulzele, Amitkumar
dc.contributor.authorDejung, Mario
dc.contributor.authorSauer, Markus
dc.contributor.authorWinner, Beate
dc.contributor.authorRose-John, Stefan
dc.contributor.authorArnold, Philipp
dc.contributor.authorSaftig, Paul
dc.contributor.authorZunke, Friederike
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutionCentro de Estudos de Doenças Crónicas (CEDOC)
dc.contributor.pblLandes Bioscience
dc.date.accessioned2022-04-04T22:38:25Z
dc.date.available2022-04-04T22:38:25Z
dc.date.issued2022-04-28
dc.description.abstractParkinson disease (PD) is a neurodegenerative disorder characterized by the abnormal intracellular accumulation of SNCA/α-synuclein. While the exact mechanisms underlying SNCA pathology are not fully understood, increasing evidence suggests the involvement of autophagic as well as lysosomal deficiencies. Because CTSD (cathepsin D) has been proposed to be the major lysosomal protease involved in SNCA degradation, its deficiency has been linked to the presence of insoluble SNCA conformers in the brain of mice and humans as well as to the transcellular transmission of SNCA aggregates. We here postulate that SNCA degradation can be enhanced by the application of the recombinant human proform of CTSD (rHsCTSD). Our results reveal that rHsCTSD is efficiently endocytosed by neuronal cells, correctly targeted to lysosomes and matured to an enzymatically active protease. In dopaminergic neurons derived from induced pluripotent stem cells (iPSC) of PD patients harboring the A53T mutation within the SNCA gene, we confirm the reduction of insoluble SNCA after treatment with rHsCTSD. Moreover, we demonstrate a decrease of pathological SNCA conformers in the brain and within primary neurons of a CTSD-deficient mouse model after dosing with rHsCTSD. Boosting lysosomal CTSD activity not only enhanced SNCA clearance, but also restored endo-lysosome and autophagy function in human and murine neurons as well as tissue. Our findings indicate that CTSD is critical for SNCA clearance and function. Thus, enzyme replacement strategies utilizing CTSD may also be of therapeutic interest for the treatment of PD and other synucleinopathies aiming to decrease the SNCA burden.en
dc.description.versionauthorsversion
dc.description.versionpublished
dc.format.extent1761690
dc.identifier.doi10.1080/15548627.2022.2045534
dc.identifier.issn1554-8627
dc.identifier.otherPURE: 42509409
dc.identifier.otherPURE UUID: 760fb1f2-5ed9-482b-b2e8-98fb72620844
dc.identifier.otherPubMed: 35287553
dc.identifier.otherWOS: 000788553600001
dc.identifier.otherScopus: 85125870193
dc.identifier.urihttp://hdl.handle.net/10362/135842
dc.language.isoeng
dc.peerreviewedyes
dc.subjectalpha-synuclein
dc.subjectcathepsin D
dc.subjectlysosomal degradation
dc.subjectlysosomal storage disorders
dc.subjectparkinson disease
dc.subjectsynucleinopathies
dc.subjectSDG 3 - Good Health and Well-being
dc.titleRecombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy modelsen
dc.typejournal article
degois.publication.firstPage1127
degois.publication.issue5
degois.publication.lastPage1151
degois.publication.titleAutophagy
degois.publication.volume18
dspace.entity.typePublication
rcaap.rightsopenAccess

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