My scientific career began with training in biochemistry, biophysical chemistry and cell biology at JW Goethe University (Germany), in the laboratory of Drs. Walter Volknandt and Herbert Zimmermann, where I established a procedure for immuno-isolation of synaptic vesicles to high purity. Synaptic vesicles govern fast neurotransmitter release, and despite intense research, not all vesicular functions are assigned to protein components. I built a comprehensive proteomic map of synaptic vesicles, and compared vesicle proteins under conditions of neuronal rest and activity. Out of several novel proteins identified, I studied the novel synaptic vesicle protein SV31, which has now been ascribed zinc transporter function in GABAergic neurons.
As a postdoc, I joined Dr. Thomas Südhof’s lab, first at UT Southwestern Medical Center, and then at Stanford University, to study α-synuclein in health and disease. Pathologically, α-synuclein mutations and overexpression cause Parkinson’s disease, and aggregates of α-synuclein are found as Lewy bodies in multiple neurodegenerative disorders. Yet, its function remained unclear. I discovered that α-synuclein has an important physiological activity at the synapse to promote SNARE-complex assembly. In collaboration with Dr. Axel Brunger’s lab, I found that native α-synuclein is monomeric and unstructured in cytosol, but forms homo-multimers on synaptic vesicles, which induce clustering of synaptic vesicles at the presynaptic plasma membrane and thereby increase local SNARE-protein concentration. The importance of this function became clear in aged synuclein knockout animals: Mice revealed reduced SNARE-complex levels, accompanied with progressive neuropathology and premature death. Thus, α-synuclein is required for ensuring proper SNARE-complex assembly at the synapse during aging.
Is neurodegeneration in Parkinson’s disease a result of losing α-synuclein’s function, or is pathology triggered by gain-of-toxic function of α-synuclein? Using a structure-function approach, I compared function and pathology of 26 α-synuclein mutants, and found that the physiological function of α-synuclein is fundamentally distinct from its neuropathological effects. Consequently, pathology in synucleinopathies is likely caused by gain-of-toxic function of α-synuclein.
In collaboration with Dr. Manu Sharma, I analyzed the role of cysteine string protein-α (CSPα) in neurodegeneration. In absence of CSPα, mice develop a neurodegenerative phenotype, which correlates with synaptic impairments, decreased levels of the SNARE-protein SNAP-25 and disrupted SNARE-complex assembly. CSPα forms a catalytically active chaperone complex with Hsc70 and SGT at the synapse. We found that this complex chaperones SNAP-25 during synaptic activity, ensuring proper functioning of SNAP-25 and SNARE-complex assembly. This activity of CSPα, similar to α-synuclein’s activity on SNARE-complexes, is required for the long-term sustenance of nerve terminals and neurons.
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 demonstrated to 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;
- by an exploratory screen early in the course of neurodegeneration, to identify yet-unknown mechanisms triggering synaptic dysfunction and degeneration.
To address these aims, we will employ an array of cutting-edge technologies, including biophysics, biochemistry, cell biology, imaging, and mouse models of neuropathology:
Investigating the dysfunction of synucleins and Munc18 at the synapse, as well as screening mouse models of neurodegenerative diseases for synaptic changes will identify pathological events happening early in the progression of the respective diseases. We envision that defining early pathological events at the synapse will provide new avenues for preventing and/or treating neurodegenerative diseases in humans.