Neurons communicate via release of neurotransmitters from presynaptic terminals. This requires intact functioning of the protein expression and trafficking machinery, of mitochondria to meet a synapses’ need for energy, of the proteasome/ubiquitin system and lysosomes to clear aged and misfolded proteins, and of the synaptic vesicle cycle to mediate continuous neurotransmission. Much evidence points to presynaptic terminals as initiation site for neurodegeneration in diseases such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, where synaptic dysfunction has been shownto precede neuron death and to occur long before neuropathological symptoms become apparent. Yet, virtually nothing is known about processes involved.
We are interested in early pathological events at the synapse which trigger neurological disorders and neurodegeneration. We will approach this topic by investigating the dysfunction of synucleins at the synapse, a protein family implicated in Parkinson’s Disease, Alzheimer’s Disease, multiple system atrophy, and dementia with Lewy bodies; by investigating the dysfunction of Munc18 at the synapse with regards to Ohtahara syndrome (early infantile epileptic encephalopathy) and mental retardation with non-syndromic epilepsy; and by an exploratory screen to identify other yet-unknown mechanisms triggering synaptic dysfunction and degeneration in various diseases. To address these aims, we will employ an array of cutting-edge technologies, including biophysics, biochemistry, cell biology, imaging, and mouse models of neuropathology.
We envision that defining early pathological events at the synapse will provide new avenues for preventing and/or treating neurodegenerative diseases in humans.