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Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinsons disease-like phenotype
Gaia Faustini (Författare), Francesca Longhena (Författare), Anna Masato (Författare), Valentina Bassareo (Författare), Roberto Frau (Författare)
URI http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-184703, URN urn:nbn:se:liu:diva-184703, DOI 10.1016/j.ymthe.2022.01.021, Identifikator http://liu.diva-portal.org/smash/get/diva2:1656643/FULLTEXT01 · url
Linköpings universitet Institutionen för fysik, kemi och biologi (Utgivare), Linköpings universitet Tekniska fakulteten (Utgivare)
utgivning
Cell Press, 2022är del av
Molecular Therapy · ISSN 1525-001630:4, 1465-1483
Bidrag, Onlineresurs
ämne
Medical and Health Sciences, Medical Biotechnology, Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy), Medicin och hälsovetenskap, Medicinsk bioteknologi, Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)Sammanfattning
Fibrillary aggregated alpha-synuclein (alpha-syn) deposition in Lewy bodies (LB) characterizes Parkinsons disease (PD) and is believed to trigger dopaminergic synaptic failure and a retrograde terminal-to-cell body neuronal degeneration. We described that the neuronal phosphoprotein synapsin III (Syn III) cooperates with alpha-syn to regulate dopamine (DA) release and can be found in the insoluble alpha-syn fibrils composing LB. Moreover, we showed that a-syn aggregates deposition, and the associated onset of synaptic deficits and neuronal degeneration occurring following adeno-associated viral vectors-mediated overexpression of human alpha-syn in the nigrostriatal system are hindered in Syn III knock out mice. This supports that Syn III facilitates alpha-syn aggregation. Here, in an interventional experimental design, we found that by inducing the gene silencing of Syn III in human alpha-syn transgenic mice at PD-like stage with advanced alpha-syn aggregation and overt striatal synaptic failure, we could lower alpha-syn aggregates and striatal fibers loss. In parallel, we observed recovery from synaptic vesicles clumping, DA release failure, and motor functions impairment. This supports that Syn III consolidates alpha-syn aggregates, while its downregulation enables their reduction and redeems the PD-like phenotype. Strategies targeting Syn III could thus constitute a therapeutic option for PD.
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Medverkan och funktion
Gaia Faustini (Författare), Francesca Longhena (Författare), Anna Masato (Författare), Valentina Bassareo (Författare), Roberto Frau (Författare)Medverkan och funktion
Linköpings universitet Institutionen för fysik, kemi och biologi (Utgivare), Linköpings universitet Tekniska fakulteten (Utgivare)Identifikator
URI http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-184703, URN urn:nbn:se:liu:diva-184703, DOI 10.1016/j.ymthe.2022.01.021, Identifikator http://liu.diva-portal.org/smash/get/diva2:1656643/FULLTEXT01 · urlhar titel
Synapsin III gene silencing redeems alpha-synuclein transgenic mice from Parkinsons disease-like phenotypeär del av
Molecular Therapy · ISSN 1525-0016del
30:4, 1465-1483utgivning
Cell Press, 2022tillhörande media
http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-184703http://dx.doi.org/10.1016/j.ymthe.2022.01.021http://liu.diva-portal.org/smash/get/diva2:1656643/FULLTEXT01Relaterad beskrivning eller innehåll
Värdpublikationanmärkning
- <p>Funding Agencies|Michael J. Fox Foundation for Par-kinsons Research, NY, USA (Target Advancement Program) [10742.01]</p>
- Published
tillhörande media
http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-184703http://dx.doi.org/10.1016/j.ymthe.2022.01.021http://liu.diva-portal.org/smash/get/diva2:1656643/FULLTEXT01Villkor för användning och åtkomst
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9qv8qd3t7cnq3sdmResursens ID / Permalänk: https://libris.kb.se/9qv8qd3t7cnq3sdm#it
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