Axonal degeneration is a shared feature of many neuropathological conditions including response to injury, exposure to neurotoxins, hereditary neuropathies, and neurodegenerative diseases. The degenerative process is active, yet little is known of the endogenous molecular pathway in neurons that promotes axonal degeneration. We have now identified the MAP kinase kinase kinase DLK and its downstream MAP kinase JNK as key components of a pathway promoting axonal degeneration. The DLK/JNK pathway is required for normal axonal degeneration in response to both axotomy and neurotoxic insult in cultured DRG neurons. In addition, DLK is required in vivo for normal axonal degeneration following axotomy of the sciatic nerve in mice. We hypothesize that the DLK/JNK pathway is central to the axonal degeneration mechanism in neurons. As such, inhibition of this pathway has therapeutic potential as a treatment for the many neurological disorders in which axonal degeneration is a prominent feature.
To test this hypothesis we will determine if:
1) the DLK/JNK pathway promotes degeneration in response to a range of neuronal insults in vitro
2) DLK promotes synaptic loss following axotomy in vivo
3) DLK promotes the degeneration of central axons following axotomy in vivo
4) pharmacological inhibition of JNK protects peripheral axons from degeneration in vivo.
These studies investigate the therapeutic potential of DLK/JNK pathway inhibition in axonopathy models.
“Regulation of Axonal Degeneration by the DLK Kinase”
NIH, RO1 NS065053 (DiAntonio, PI; Milbrandt, Co-PI)
This project characterizes the roles of DLK in axonal degeneration.
Miller RB, Press C, Daniels RW, Sasaki Y, Milbrandt J, DiAntonio A. A DLK-dependent axon self-destruction program promotes Wallerian degeneration. Nature Neuroscience. 12:387-389 (2009).
Patent application: USPTO 12/548,411, “Modulation of the DLK/JNK Pathway as a Method for Inhibiting Axonal Degeneration”