“It takes two to tango: Alpha-synuclein and p25α in MSA ... · Markus Zweckstetter, PhD, German...
Transcript of “It takes two to tango: Alpha-synuclein and p25α in MSA ... · Markus Zweckstetter, PhD, German...
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“It takes two to tango: Alpha-synuclein and p25α in MSA pathogenesis”
:aSynfibrils
:oligodendroglialaSyn:p25α
:aggregatedoligodendroglialaSyn
FACT:
² Oligodendrocytes in the braincontainp25α,butverylowlevelsofendogenousalpha-synuclein(aSyn).
HYPOTHESIS:
² Can this miniscule amount of
o l i g o d e n d r o g l i a l a S y n b etransformedtopathologicalproteinaggregates upon challenge withextracellularaSynfibrils?
?
- supported study by
Dr Maria Xilouri
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StudyDesignandScope
Ourresearchaimedto:
Ø Iden%fythemechanismsthatcontroltheaggrega<onofalpha-synucleininoligodendrocytesandassesstheroleofp25αinthisprocess.
Ø DevelopnovelcellularandanimalmodelsofMSAbasedontheseedingof%nyamountsofaggregatedaSynintooligodendroglialcells,whichnormallycontainnegligibleamountsofendogenousaSyn.
EventsleadingtoMSAprogression:
Krismer@Wenning,2017,NatureReviewsNeurology,13,232–243
MSAHealthy
• Relocaliza%on of p25α fromthe myelin sheath to theoligodendroglialcellsoma
• Aggrega%on of pathologicalalpha-synuclein (aSyn) specieswithinoligodendrocytes :p25α
:aggregatedoligodendroglialaSyn:endogenousoligodendroglialaSyn
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Addi<onofpathologicalaSynfibrilsinoligodendrocytesresultsin:
ü Robust recruitment of endogenous
alpha-synuclein(rataSyn)andresultantoligodendroglial cell dysfunc%on,dependent on the minute amunts ofendogenousaSyn.
ü Demyelina<on(inprimaryculturesandin the mouse brain), which aredependent on the presence ofendogenousalpha-synuclein,sincemiceknock-out for aSyn (KO-aSyn) areprotected.
Ø p25α plays a crucial role in theestablishment of alpha-synucleinpathology.
MajorFindings
Mavroeidietal,ActaNeuropathol.2019doi:10.1007/s00401-019-02014-y2019
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Ø Our immediatepriori%es include themodula<onofp25α levelsandits subcellular localiza<on and the inves<ga<on of earlyoligodendrocyte phenotypes in the MSA-like models we havedeveloped in order to iden%fy factors that may alter diseaseprogression.
Ø In parallel, we are studying the proteoly<c pathways that degradebotholigodendroglialalpha-synucleinandp25α,whichmayrepresentpoten%altherapeu%ctargets.
Ø In future studieswe seek togenerate iPSC-derivedoligodendrocytesfrom MSA and Parkinson’s disease (PD) pa<ents in an aJempt toiden%fy puta%ve factors thatmay trigger the accumula%on of alpha-synucleinselec%velyinoligodendrogliaofMSAandnotofPDpa%ents.
FuturePerspec\ves
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Major contributors BRFAA Panagiota Mavroeidi, MSc Leonidas Stefanis, MD, PhD
Collaborators Poul-Henning Jensen, MD, PhD, University of Aarhus, Faculty of Medicine, Denmark Markus Zweckstetter, PhD, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany Stefan Becker, PhD, Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry Benoit Giasson, PhD, Center for Translational Research in Neurodegenerative Diseases, University of Florida Nadia Stefanova, MD, PhD, Medical University of Innsbruck
v The scientists are grateful to for a grant in
2016 supporting the study
Acknowledgements