Our lab is interested in elucidating initiator mechanisms of neurodegenerative diseases. A better understanding of presymptomatic disease biology will lead to the development of more effective treatments for these devastating illnesses. 

The following central themes guide our research:

Selective vulnerability of specific neuronal subtypes in different neurodegenerative diseases

This selective vulnerability is what gives rise to the specific set of symptoms in each type of neurodegenerative disease. For example in ALS (amyotrophic lateral sclerosis), certain motor neurons of the brain and spinal cord that control our muscles are lost, leading to paralysis, whereas in Parkinson's disease it is dopaminergic neurons of the substantia nigra that are critical for movement initiation. The past decade has witnessed an explosion in the identification of genes associated with causation or increased risk for these different diseases, but we still do not understand why mutations in certain genes cause the selective degeneration of specific neuronal types. We aim to discover which features of neuronal identity impart their specific vulnerabilities to certain mutations. 

Common mechanisms of neurodegeneration shared across diseases

On the other hand, several common themes have emerged from the study of neurodegenerative diseases such as proteostasis, mitochondrial health, and neuroinflammation, suggesting there exist mechanisms of neurodegeneration that are shared across diseases. Where do disease mechanisms intersect or converge? How do neurons undergoing different types of stress monitor their overall health status and integrate information on their current condition? 

The neuronal stress response in neurodegenerative disease

The launching point for our research centers around dual leucine zipper kinase or DLK which is a critical regulator of the neuronal stress response to injury. Although the DLK stress response has been more extensively studied in the context of acute physical injury such as nerve crush or transection, we have found that it also becomes activated in neurodegenerative disease. DLK signaling directs a transcriptional program allowing the neuron to respond to the injury. We are interested in better understanding (1) the mechanisms activating DLK signaling, (2) how and where this pathway fits in with other pathways of organelle-specific stress, and (3) the factors influencing the final outcome for the cell, e.g. degeneration or survival.

Intercellular communication in neurodegenerative disease pathogenesis

It has become increasingly clear from studies using conditional expression of disease-associated genes in neurons versus glial cell types that most neurodegenerative diseases result from a combination of cell-autonomous and non-cell-autonomous factors. We aim to study intercellular communication between cells of the central nervous system during disease pathogenesis, and how these cell-cell interactions influence disease progression and spreading.

To address these questions, we use a combination of techniques including mouse genetics and the generation of transgenic mice using CRISPR/Cas9-assisted knock-in, wide scale imaging of cleared whole brain tissue, in vivo studies in mouse models of disease, next generation sequencing techniques including single-cell analysis, as well as in vitro studies in iPSC-derived human neurons.

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