The intricate functioning of neuronal synapses is crucial for the communication between neurons. Dysregulation of synaptic processes has been implicated in various neurological disorders, including Parkinson's disease. Alpha-synuclein, a presynaptic protein, has garnered attention due to its involvement in the formation of protein aggregates known as Lewy bodies, a hallmark of Parkinson’s disease. Recent research suggests that liquid-liquid phase separation (LLPS) and the subsequent formation of condensates could play a critical role in alpha-synuclein aggregation. To gain a comprehensive understanding of this phenomenon, it is essential to understand how alpha-synuclein phase separation is regulated within the biological context.

We have identified that alpha-synuclein phase separation is regulated by a synaptic protein partner, namely VAMP2. We now aim to comprehensively characterize the formation, dynamics, and properties of alpha-synuclein condensates involving the following objectives.

Molecular Mechanisms: VAMP2 is a key synaptic protein involved in vesicle fusion but seems to elucidate additional non-fusogenic roles in conjunction with alpha-synuclein. We aim to characterize the underlying molecular regulation, in particular the region and structure specific changes. Furthermore, we are investigating the impact of lipid membranes in the physiological function of alpha-synuclein LLPS and their implication in disease.

Assess Synaptic Impact: Using iPSC derived neuron models we evaluate the functional consequences of alpha-synuclein condensates and their regulation by VAMP2 on synaptic physiology. We investigate whether the presence of condensates influences neurotransmitter release, synaptic plasticity, and other key synaptic processes and proteins.

Identify Therapeutic Targets: Investigating VAMP2-mediated alpha-synuclein phase separation we will gain new insights into potential therapeutic targets for neurodegenerative disorders, elucidating the regulatory pathways governing alpha-synuclein condensates. Exploring the possibility to modulate the interaction between VAMP2 or other associated proteins with alpha-synuclein will deliver concepts to prevent or mitigate aberrant condensate formation.

Neurodegenerative disorders like Parkinson’s disease are characterized by the accumulation of misfolded proteins. This project could provide critical insights into the early events that contribute to alpha-synuclein aggregation, offering new avenues for therapeutic intervention. The identification of molecular players involved in alpha-synuclein condensate regulation may lead to the development of targeted therapies that aim to prevent or disrupt aberrant condensate formation, directly targeting disease progression.