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Séminaire impromptu - Armin GieseAnle138b, a novel oligomer modulator for the treatment of neurodegenerative diseases

Abstract :

Séminaire ouvert à tous dans le cadre du DU
Université Victor Segalen-Bordeaux 2 / Année 2013
Inscrivez vous cette année au Diplôme Universitaire "Maladies Neurodégénératives"
An university diploma: Neurodegenerative disorders
Special Course : Neurodegenerative disorders, Translational Research : from Physiopathology  to therapeutic approaches Translational research: from pathophysiology to therapeutic approaches

In neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and prion diseases, deposits of aggregated disease-specific proteins are found. Oligomeric aggregates are presumed to be the key neurotoxic. Aggregation of α-synuclein is involved in the pathogenesis of PD. Studies of in vitro aggregation of α-synuclein are rendered complex because of the formation of a heterogeneous population of oligomers. With the use of confocal single-molecule fluorescence techniques, we demonstrate that small aggregates (oligomers) of α-synuclein formed from unbound monomeric species in the presence of organic solvent (DMSO) and iron (Fe(3+)) ions have a high affinity to bind to model membranes and form ion-permeable pores. Pathological oligomers represent a target for disease-modifying therapy. Based on this reasoning, we developed the novel oligomer modulator anle138b, based on a systematic high-throughput screening campaign combined with medicinal chemistry optimization. In vitro, anle138b blocked the formation of pathological aggregates of prion protein (PrPSc) and of α-synuclein (α-syn), which is deposited in PD and other synucleinopathies such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Anle138b showed structure-dependent binding to pathological aggregates and strongly inhibited formation of pathological oligomers in vitro and in vivo both for prion protein and α-synuclein. Both in mouse models of prion disease and in three different PD mouse models, anle138b strongly inhibited oligomer accumulation, neuronal degeneration, and disease progression in vivo. Anle138b had no detectable toxicity at therapeutic doses and an excellent oral bioavailability and blood–brain-barrier penetration. Our findings indicate that oligomer modulators provide a new approach for disease-modifying therapy in these diseases, for which only symptomatic treatment is available so far. Moreover, our findings suggest that pathological oligomers in neurodegenerative diseases share structural features, although the main protein component is disease-specific, indicating that compounds such as anle138b can have a broad spectrum of activity in the treatment of different protein aggregation diseases.

 

Wassilios Meissner

Biosketch


Prof. Dr. Armin Giese studied medicine in Kiel (Germany) and London (UK). During this time, he obtained a BSc in neurobiology at University College London in 1992. He received scholarships from the German National Scholarship Foundation and from the GermanAcademic Exchange Service („DAAD"). He started his clinical training in the field of neuropathology at the University of Göttingen in 1994 and finished his doctoral thesis «summa cum laude» in 1999. In 2000 he moved to the Ludwig-Maximilians-University in Munich. He became consultant in neuropathology in 2003 and full professor for neuropathology in 2008. His scientific focus is the role of protein aggregation inneurodegenerative diseases. He developed new high-throughput methods for protein oligomer detection and for the screening of aggregation inhibitors based on single-particle spectroscopy. Using this technology, he identified novel aggregation inhibitors with excellent medicinal chemical properties and high in vivo efficacy.