2008 Pilot Projects

2008 Awards

Descriptions and progress of each award can be found in the project details.

Pilot project teams include Hope Center faculty members and others. For more about Hope Center faculty click on their names below.

Inhibition of the DLK/JNK Pathway as a Therapeutic Target for Axonopathy

Principal Investigator: Aaron DiAntonio (WashU Developmental Biology)
Co-investigator: Jeffrey Milbrandt (WashU Genetics)

Project details


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.

Grants and Awards

“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.

Intellectual Property

Patent application: USPTO 12/548,411, “Modulation of the DLK/JNK Pathway as a Method for Inhibiting 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).

Updated January 2014

Functional RNAi screen to identify pathways essential for protein aggregate clearance and degradation

Principal Investigator: Conrad (Chris) Weihl (WashU Neurology)
Co-investigator: David Piwnica-Worms (formerly WashU Radiology)

Project details


Protein aggregation is the pathologic basis of many neurodegenerative diseases. Protein aggregates form when a protein, either mutant or endogenous, assumes an abnormal conformation and escapes normal degradative pathways. This results in the accumulation of protein inclusions that are deleterious to the cell and underlies disease pathogenesis. Approaches aimed at decreasing protein aggregate formation or disaggregating preformed protein aggregates have proven to be reasonable therapeutic targets in some neurodegenerative disease models. However, an alternative approach may be to enhance the degradation or “clearance” of preformed protein aggregates.  This proposal aims to identify novel pathways involved in the sequestration and clearance of intracellular protein aggregates via autophagy. These novel pathways will serve as potential therapeutic targets aimed at decreasing aggregate burden in a cell.

To do this we will utilize a prototypical aggregate prone protein, the expanded polyglutamine (polyQ) repeat containing protein. Expanded polyQ repeats are present in many aggregate prone proteins associated with neurodegenerative diseases such as mutant huntingtin protein in Huntington’s disease, ataxin-3 in spinocerebellar ataxia type-3 and the androgen receptor in spinobulbar muscular atrophy. While an unexpanded polyQ repeat containing protein is soluble, once a polyQ repeat expands to a critical number, it develops the propensity to misfold, form fibrils and aggregate into inclusion bodies. We constructed two luciferase based reporter constructs 1) a non-aggregating polyQ19-luciferase and 2) an aggregate prone expanded polyglutamine containing luciferase, polyQ80-luciferase. Enhancement of autophagy via the mTOR inhibitor rapamycin or nutrient deprivation selectively decreases the polyQ80-luciferase activity as compared with polyQ19-luciferase in cells. Our preliminary studies show that these reporter constructs are sensitive to autophagic activation and inhibition in a time and concentration dependent manner. Moreover, these reporters can be used in vivo to measure the autophagic clearance of protein aggregates in live animal tissue.


Fuentealba RA, Marasa J, Diamond MI, Piwnica-Worms D, Weihl CC. An aggregation sensing reporter identifies leflunomide and teriflunomide as polyglutamine aggregate inhibitors. Human Molecular Genetics. 21(3):664-80 (2012).

Updated June 2017

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