Rewatch this 3P-Seminar
Nora Bengoa-Vergniory, Research fellow at Oxford University discussed ‘CLR01 protects dopaminergic neurons in vitro and in vivo in mouse and human models’ and Anke Van der Perren, Postdoc at KU Leuven presented ‘In vivo characterization of distinct patient-derived alpha-synuclein strains’
Nora’s presentation featured:
Molecular tweezers have shown high potential as anti-aggregation agents targeting positively charged residues of proteins undergoing amyloidogenic processes. We therefore investigated whether the molecular tweezer CLR01 could ameliorate phenotypes in vitro and in vivo in human and mouse models of PD. In vitro, CLR01 decreased alpha-synuclein aggregation and its associated toxicity in induced pluripotent stem cell-derived dopaminergic cultures. We then tested CLR01 in vivo in a humanized alpha-synuclein overexpressing mouse model; mice treated for two months at 12 months of age, exhibited an improvement in motor defects and a decreased oligomeric alpha-synuclein burden. Finally, CLR01 was able to reduce alpha-synuclein-associated pathology in mice injected with either mouse or human alpha-synuclein aggregates into the striatum or substantia nigra. Altogether, these results highlight that CLR01 represents a possible disease-modifying therapy for PD.
Anke’s presentation discussed:
The molecular hallmark of synucleinopathies such as Parkinson’s, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are large αSYN-rich deposits suggestive of one molecular event causing distinct disease phenotypes. We hypothesized that distinct phenotypes in synucleinopathies might correlate to heterogeneity in αSYN strains in patients. Here, we studied the relationship between αSYN transmission, neurotoxicity and neuroinflammation using advanced experimental cellular and rodent models. The αSYN assemblies were purified and amplified from human brain samples of PD, MSA and DLB patients. We found that MSA strains show several similarities with Parkinson’s strains, but are significantly more potent in inducing motor deficits, nigrostriatal neurodegeneration, αSYN pathology, spreading, and inflammation, reflecting the aggressive nature of this disease. In contrast, DLB strains displayed no or only very modest neuropathological features under our experimental conditions.