Position title: Assistant Professor
Neuronal Cell Biology, Neurodegenerative disease, Neurodevelopment
- Ph.D., Northwestern University
- Research Fields
- Cell biology, development, neuro and behavioral genetics
- Lab Website
Cargo-specific retrograde axonal transport Neurons rely on the efficient and highly regulated transport of cargos between the cell body and axon terminal to form and maintain neural circuits. These large cells can have axonal projections that reach approximately a meter from the cell body in humans, if not longer. To carry necessary proteins and organelles throughout this enormous volume, these cells rely heavily on their intracellular transport machinery. Disruptions to cargo transport are thought to underlie many neurodegenerative diseases; however, we still have little understanding of how this process is controlled in the complex, intracellular environment of the neuron. Using forward genetics, we have identified several zebrafish strains with phenotypes indicative of disrupted transport of cargo from the distal axon to the cell body. To date, all mutants we have identified using this approach are the result of nonsense mutations in proteins known to interact with the retrograde motor, cytoplasmic dynein. Two of these lines have been the subject of projects delineating a role for the disrupted proteins in the retrograde movement of lysosomes and an activated kinase in one case and mitochondria in the other. In addition to these mutants, we have also isolated 6 as of yet uncharacterized mutant lines which will form the basis of independent research projects in the lab.
In addition, we also use reverse genetic approaches to identify novel genes important for the retrograde transport of various cargos in the lab. The end goal for this section of our research program is to define the mechanisms of cargo-specific retrograde transport for axonal cargos. This will allow us to both understand the basic biology and better delineate the pathology associated with neurodegenerative disease.
Regulation of mitochondrial retrograde transport in axons
In order to form and maintain neural connections, neurons extend long axonal processes to make contact with partners both in close proximity and at great distances. Supporting this type of large, metabolically active structure requires a great deal of energy supplied largely by mitochondria. Therefore, the proper localization of mitochondria in axons is thought to be critical for both the formation and maintenance of axons. In addition, in order for information to be transmitted via action potential in axons, neurons need to be rapidly depolarized and subsequently hyper polarized to ready themselves for the next burst of activity. Largely this re-polarization of the neuron is accomplished by ATP-dependent pumps. As mitochondria are the primary source for ATP locally, the function of the neuron relies on the positioning of this organelle near sites of high ion flux to return the neuron to a resting state.
In addition to being critical for axonal health, mitochondria must also be actively transported to maintain their own health and function. Mitochondria move together to fuse and apart during the process of fission. These so called “mitochondrial dynamics” are essential for the maintenance of mitochondrial health. Interestingly, mitochondrial dynamics are tightly tied to transport molecularly. Proteins involved in mitochondrial dynamics, such as Mitofusin and Drp1, are also known to regulate mitochondrial transport by molecular motors.
We are particularly interested in how mitochondria attach to and are moved by the cytoplasmic dynein retrograde motor complex. Dynein walks unidirectionally towards microtubule minus ends. In axons, microtubules are polarized with their minus ends facing the cell body. This means that dynein is responsible for moving mitochondria in the direction of the cell body. How mitochondria attach to this motor in a regulated fashion to be moved to the right place at the right time is a topic of primary focus for our lab. Other related questions include: 1) the mechanics of mitochondria-dynein attachment; 2) the of impact retrograde mitochondrial transport disruption on mitochondrial homeostasis; and 3) the interplay between mitochondrial dynamics and mitochondrial transport in axons.
Our lab uses zebrafish larvae and IPSC-derived sensory neurons to address these questions using complimentary approaches including in vivo imaging, genetics, and protein biochemistry in vivo.
Mandal A, Wong HTC, Pinter K, Mosqueda N, Beirl A, Lomash RM, Won S, Kindt KS, and Drerup CM. 2020. Retrograde mitochondrial transport is essential for organelle distribution and health in zebrafish neurons. J. Neurosci. JN-RM-1316-20; DOI: https://doi.org/10.1523/JNEUROSCI.1316-20.2020
Drerup CM, Herbert AL, Monk KR, Nechiporuk A. 2017. Regulation of mitochondria-dynactin interaction and mitochondrial retrograde transport in axons. eLife. 10.7554/eLife.22234. PMID28414272. Drerup CM, Nechiporuk A. 2016. In vivo analysis of axonal transport in zebrafish. Methods Cell Biol. 131:311-329. PMID26794521.
Drerup CM, Nechiporuk A. 2013. JNK-interacting protein 3 mediates the retrograde transport of activated c-Jun N-terminal Kinase and lysosomes. PLoS Genetics. 9(2): e1003303. PMID23468645