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Written By Sao Bettencourt – MSA Coalition Travel Award Winner

Thanks to the support of MSA Coalition, I have attended in September (1-4th) the “Synuclein Meeting 2019: Where we are and where we need to go” in Ofir, a city in the outskirts of Porto, Portugal.

This meeting brought together over 300 participants, including leading experts in the field of Synuclein and Synucleinopathies, from both academia and industry, as well as a broad community of junior scientists. This meeting was organized in an unusual format, consisting mostly of round-table discussions, with just a few oral presentations and keynote lectures, to create more opportunities to discuss the major questions in the field. There were also two poster sessions (over 130 posters in total), during which I have presented a poster with our recent research findings on MSA (summarize below).

Attending this meeting was beneficial for me and our research group at several levels:

  1. Being able to disseminate and discuss our exciting findings on epigenetics of MSA;
  2. Having the chance to hear from leading experts, learn extensively and update my knowledge about
    ongoing research on Synuclein and Synucleinopathies (including MSA);
  3. Having the chance to meet personally and engage with both senior and junior scientists in the field,
    and discuss science as well as career development;
  4. Having the chance to network with researchers I have met/worked with before as well as with
    potentially new collaborators.

During the conference, MSA was given relevant attention in multiple occasions:

On the first day of the conference, there was a main talk by Gregor Wenning, who gave an overview about MSA, from clinical aspects to highlighting several recent studies trying to develop drugs that can then be taken into clinical trials. He mentioned that at least 25 compounds are already being or about to be tested in MSA.

MSA was also given major attention on “Roundtable 10 – Spreading of alpha-synuclein – relevant or epiphenomenon?”, chaired by Glenda Halliday and having Jiayi Li, Jeff Kordower, Donato Di Monte, Glenda Halliday, Veerle Baekelandt, and Gregor Wenning as speakers. The major discussion point was whether in Synucleinopathies the spreading of alpha-synuclein occurs in a prion-like manner. There was no overall consensus in this matter.

There were also about 15 posters mentioning MSA, some of which having MSA as the main research focus while others would use MSA as a comparison group together with other neurodegenerative diseases. From those, I would like to highlight our own poster:

PO42 – by Conceição Bettencourt et al. (United Kingdom), “DNA METHYLOME ANALYSIS IN POST-MORTEM BRAIN TISSUE OF MULTIPLE SYSTEM ATROPHY PATIENTS”. In the poster we have presented our recent findings on epigenetics of MSA. Despite extensive research, the regional vulnerability of the brain to MSA pathology remains poorly understood. Genetic, epigenetic and environmental factors have been proposed to explain which brain regions are affected by MSA, and to what extent. We explored for the first time epigenetic changes in post-mortem brain tissue from MSA cases. We conducted a multi-phase case-control study, and profiled genome-wide DNA methylation (Illumina EPIC arrays) in white mater from three brain regions characterized by severe-to-mild pathology burden in the MSA mixed subtype (cerebellum, frontal lobe and occipital lobe). We observed that DNA methylation levels in HIP1, LMAN2, MOBP, among other loci were perturbed in MSA mixed subtype, and also to variable degrees in the other pathological subtypes (MSA OPCA and SND). We also identified several molecular signatures significantly associated with MSA (disease status and pathological subtypes), and with neurodegeneration in the cerebellum. Importantly, the

DNA methylation signature having the strongest association with MSA included SNCA, the gene encoding α- synuclein. Altogether, our results provide the first evidence for DNA methylation changes contributing to the molecular processes altered in MSA, and highlight potential novel routes for diagnosis and therapeutic interventions.

I would also like to highlight several examples of excellent research done by others, including:

PO09 – by Antonio Heras-Garvin et al. (Austria), “HYPOXIA, A POSSIBLE PATHOGENIC FACTOR IN MSA AND PD”, investigating a possible role for hypoxia as a pathogenic factor in MSA and PD. The authors observed a significant accumulation of the hypoxic marker HIF2α in MSA and are pursuing this further with additional investigations.

PO17 – by Miguel Lemos et al. (Austria), “COMBINED ANTI-Α-SYNUCLEIN THERAPY FOR DISEASE MODIFICATION IN MULTIPLE SYSTEM ATROPHY” testing disease modification properties of two compounds in a transgenic mouse model overexpressing α-Synuclein in oligodendrocytes. One of these compounds consist of short immunogenic peptides (AFFITOPEs), carrying a sequence that mimics the original α- Synuclein epitope, and the other (Anle138b) is an aggregation inhibitor. The authors confirmed the efficacy of the single therapy with AFFITOPEs or Anle138b, observing motor improvement, rescue of dopaminergic neurons, reduction in α-Synuclein oligomers, decrease of GCIs density, and decreased levels of microglia activation. The combination of Anle138b+AFFITOPEs has also shown benefits but no cumulative beneficial effects were achieved by combining the two. Interesting results in this mouse model that certainly warrant further investigation.

PO35 – by Violetta Refolo et al. (Austria), “NEUROINFLAMMATORY PATHWAYS INVOLVED IN THE SELECTIVE NEURODEGENERATION OBSERVED IN A TRANSGENIC MOUSE MODEL OF MULTIPLE SYSTEM ATROPHY”, investigating the pathways involved in the neuroinflammatory region-specific events occurring, over the disease course, in a transgenic mouse model of MSA. Their findings suggest an important role of the early, alpha-synuclein-triggered neuroinflammation for the progressive neurodegeneration of the substantia nigra in this mouse model.

PO44 – by Jonas Folke et al. (Denmark), “PERIPHERAL IMMUNE CELLS CORRELATE TO DISEASE PROGRESSION IN MULTIPLE SYSTEM ATROPHY AND PARKINSON’S DISEASE”, evaluating peripheral immune cell changes in MSA and PD in a longitudinal manner, and showing changes in immune cells in both MSA and PD patients.

PO75 – by Vincenzo Donadio et al. (Italy), “INTRANEURAL SKIN NERVE Α-SYNUCLEIN DEPOSITS IN MULTIPLE SYSTEM ATROPHY”, who reports that neuritic inclusions of phosphorylated α-synuclein in somatic skin nerves can represent a sensitive biomarker for MSA.

PO116 – by Teresa Torre-Muruzabal et al. (Belgium), “CHARACTERIZATION OF TWO DISTINCT ALPHA- SYNUCLEIN STRAINS IN A MOUSE MODEL FOR MULTIPLE SYSTEM ATROPHY”, examining whether different α-synuclein strains might exert distinct pathologies in an animal model of MSA. They found distinct histopathological and behavioural phenotypes in vivo.

PO118 – by Ilaria Poggiolini et al. (United Kingdom), “DEVELOPMENT OF ALPHA-SYNUCLEIN SEEDING ASSAY AS AN EARLY, PROGRESSION AND STRATIFYING BIOMARKER FOR SYNUCLEINOPATHIES”, examining aSyn RT-QuIC assay in brain tissue from Multiple System Atrophy (MSA) in parallel to PD patients in order to see if it can stratify between the different synucleinopathies. The authors found substantially different kinetic properties on RT-QuIC in MSA vs. PD, and suggest the aSyn RT-QuIC assay has potential as an early, differential test for prodromal disease.