Objective: To develop small molecular weight compounds (SMEs) as disease-modifying agents, which are designed to arrest or even reverse the aggregation process of alpha-synuclein (aSyn) protein.

Background: The aberrant accumulation of alpha-synuclein (aSyn) aggregates is a common pathological feature of Parkinson’s disease (PD) and other synucleinopathies. An increasing amount of evidence from cellular and animal models indicates that the active processes of aSyn aggregation and fibril growth are actually contributing to neuronal toxicity. Agents and small molecules that can interfere with these processes and either disaggregate or inhibit the formation of β-sheet-rich aggregates are therefore expected to have therapeutic effects.

Methods: SMEs were synthesized based on the rationale of the Morphomer™ Technology platform developed by AC Immune in which compounds are designed to target and modify β-sheet structures of aggregation-prone proteins rendering them harmless. SMEs are evaluated in vitro systems for their ability to reduce or inhibit aSyn aggregation by traditional methods for monitoring β-sheet content such as Thioflavin T-based assays as well as the effects on the morphology of recombinant fibrils visualized by electron microscopy. SMEs were further characterized by their ability to rescue neuroblastoma cells and primary neurons from aSyn-mediated toxicity. Finally, the efficacy of selected compounds was evaluated in transgenic (Tg) mice overexpressing aSyn.

Results: New SMEs have been identified with the potential to inhibit aSyn aggregation and alter the conformation of aSyn aggregates. Importantly, these SMEs can rescue neurons from aSyn-induced toxicity and reduce the burden of intracellular aSyn aggregates in brains of treated Tg mice. Biomarkers for neuroinflammation and synaptic connectivity as well as the pathways involved in clearance of misfolded proteins and protein quality control have been evaluated to shed light into the molecular pathways involved into the reversal of aSyn-induced toxicity by the SMEs.

Conclusions: The data from this battery of in vitro and in vivo assays show that the SMEs have a dual function, arresting the fibrillation process of aSyn into non-toxic species and reducing β-sheet content of preformed aSyn aggregates. Such small molecule compounds hold promise in providing therapeutic benefit for PD and related synucleinopathies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/targeting-alpha-synuclein-aggregation-for-the-treatment-of-parkinsons-disease/