Konrad Zinsmaier

Professor, Neuroscience

The brain’s extraordinary computing power that put mankind on the moon is derived from neural networks that are formed by wiring billions of individual nerve cells (neuron) through trillions of connections. Wiring individual neurons into a network is accomplished by specialized interfaces, termed synapses, which transmit information on a sub-millisecond scale from one neuron to another.  Synapses harbor key mechanisms of processing and computing information in the brain, and ultimately control all our thinking, feeling and movement. 

My laboratory has a long-standing interest in understanding molecular mechanisms that mediate, modulate, and/or maintain synaptic function. Synapses require complex molecular machineries to ensure rapid information transfer and computation. Remarkably, despite their complexity, synapses exhibit not only an extraordinary speed and precision but also an autonomy and durability that is very unusual. To decipher the molecular mechanisms underlying synaptic function, we use genetically modified Drosophila as a model system and study effects on synaptic function that are induced by mutations in critical components of the synaptic machinery. Abnormal synaptic function is assayed by a variety of techniques including electrical recordings, electron microscopy, confocal microscopy and live imaging. 

Research Project 1

Effective synaptic function requires numerous protein-protein but also protein-lipid interactions that are still poorly understood. We found that the negatively charged lipid phosphatidylserine (PS) is critical for neurotransmitter release. We speculated that the presynaptic membrane requires high PS levels to facilitate synaptic vesicle fusion by the Ca2+ sensor protein Synaptotagmin to release neurotransmitter. Consistently, we found that normal PS levels at the presynaptic membrane are required for neurotransmitter release and controlled by an evolutionary conserved P4-ATPase flippase. We also found that PS levels are controlled by at least two signaling pathways whose dysfunction has been implicated to cause or contribute to certain forms of Autism Spectrum Disorders, Angelman Syndrome, and Alzheimer Disease.

Research Project 2

Supplying synapses with energy is vital for sustaining synaptic function.  However, we know little about mechanisms that transport mitochondria, the cell’s “power plants”, to synapses and maintain there their function. A better understanding is urgently needed because even slight impairments of mitochondrial function or distribution can cause or intensify neuropathy, neurodegeneration, and/or paraplegia. 

We hypothesize that the evolutionarily conserved mitochondrial GTPase Miro is a central integration node for multimodal signals that controls distinct mechanisms including mitochondrial transport, mitochondrial fusion & fission and autophagy. We discovered that Miro is critical for mitochondrial transport into axons and dendrites. Specifically, we found that Miro provides a switch to increase the use of kinesin motors during antero- and the use of dynein motors during retrograde transport.  We also found that that Miro’s ability to bind calcium is critical to keep mitochondria alive at synapses, likely to arrest transport in order to transfer new lipids and proteins from another organelle. Finally, we found that Miro controls a mitochondrial quality control mechanism that targets dysfunctional mitochondria for degradation. Since neurons are especially vulnerable to impairments of mitochondrial function, a better understanding of Miro is likely critical for treating a number of mitochondrial diseases in humans including Optic Atrophy, Charcot-Marie-Tooth Type 2A, Retinitis Pigmentosa, Parkinson’s Disease and many others.