Research

Maintenance of neurotransmission depends on the availability of functional synaptic proteins. However, synapses are often located far from their cell bodies and axonal transport may be too slow to handle the local demand of biomolecules. Our work and that of other labs has shown that an elaborate machinery active at the synapse is involved in mediating synaptic transmission and the proteins involved are used and reused during several rounds of exo- and endocytosis. Hence, activity-dependent decline in protein function may eventually result in synaptic demise, a process directly relevant to neuronal disease. Our discoveries have revealed the local mechanisms that neurons have in place to turn-over the pool of synaptic proteins and replace the damaged components. Interestingly, by analyzing these processes we also uncovered key mechanisms that are active in neurodegenerative disease.

Healthy synapses are coping with stress and protein misfolding but can apparently not do so anymore in neurodegenerative disease and ageing. Our lab has shown that during neuronal stimulation, an elaborate machinery, specifically active at the synapse, is involved in

• producing energy to promote continued synaptic transmission (Verstreken et al. Neuron 2005 and Vos et al. Science 2012), and
• mediating the turnover of synaptic proteins and organelles that accrue damage (Verstreken et al. Cell 2002; Uytterhoeven et al. Cell 2011 and Uytterhoeven et al. Neuron 2015).

Defects in these processes result in activity-dependent decline in protein and organelle function and result in synaptic and neuronal demise.

Our work has shown that the synapse-specific processes we study are directly relevant to mechanisms of Tau-induced synaptic and neuronal decline (Zhou et al. Nature Comms 2017; McInnes et al. Neuron 2018 and Largo-Barrientos et al. Neuron 2021) and Parkinson’s disease (Soukup et al. Neuron 2016; Morais et al. Science 2014; Haddad et al. Mol Cell 2013; Matta et al. Neuron 2012).

What is also important is that not all cells are equally affected in disease and recent contributions from our group are shedding light on how specific cell types are contributing (Davie et al. Cell 2018; Valadas et al. Neuron 2018; Pech et al., submitted).

In the past 10 years, our lab uncovered that

• Vitamin K2 acts as an alternative electron transport molecule in mitochondria (similar to the role of Vitamin K2 in the bacterial membrane), and that this can be used to alleviate the defects in models of Parkinson’s disease (Vos et al. Science 2012)
• Tau, a protein implicated in more than 20 neurodegenerative diseases binds to and clusters synaptic vesicles by interacting with Synaptogyrin-3, and that lowering Synaptogyrin-3 dosage rescues Tau-induced cognitive decline in mice (Largo-Barrientos et al. Neuron 2021)
• synapses harbor specific and local mechanisms to deal with protein turnover. Our lab was the first do discover the mechanism of synaptic vesicle protein turnover (Uytterhoeven et al. Cell 2011) and the first to find a synapse-specific mechanism of autophagy (Soukup et al. Neuron 2016).

Current research in the lab now aims to

• elucidate the fundamental mechanism of continued synaptic activity under conditions of stress using new and innovative screens;
• understand how specific cellular subtypes of the brain are affected based on single-cell omics approaches and
• exploit this knowledge to halt or slow disease progression using new models of disease and the design of new drug modalities. Consequently, several of our discoveries are also currently being explored in a clinical and translational context.