“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

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

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

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

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