What we do

TDP-43 Proteinopathies

Amyotropic lateral sclerosis (ALS), Frontotemporal lobar degeneration (FTLD), and Alzheimer's disease are devastating aging-related neurodegenerative diseases.

ALS is characterized by degeneration of motor neurons in the brain and spinal cord, resulting in neurogenic muscle wasting, paralysis, and death. Nearly 95% of ALS cases have pathology featuring phosphorylated inclusions of the TDP-43 protein in neurons and glial cells. Furthermore, mutations in the gene coding for TDP-43 have been shown to cause some cases of ALS, indicating normal TDP-43 is critical for neuronal health.

FTLD is the second most common presenile dementia after Alzheimer's disease. About 50% of patients diagnosed with FTLD have TDP-43 positive inclusions (FTLD-TDP), and TDP-43 dysfunction has been implicated as a cause or contributor to FTLD-TDP.

Alzheimer's disease is the most common aging-related dementia disorder, and is defined by accumulation of amyloid beta plaques and tau neurofibrillary tangles. However, more than half of patients with Alzheimer's disease also exhibit TDP-43 aggregates in disease affected neurons, and the presence of TDP-43 in patients correlates with worsened clincial and neuropathological outcomes.

Our research approaches

We use several model systems ranging from simple invertebrates to mammalian primary neurons and human pathological tissue to explore the underlying biology of TDP-43 proteinopathies and to develop new therapeutic strategies.

Neurodegenerative disease model C. elegans exhibit:

  • Progressive movement dysfunction

  • Degeneration of motor neurons

  • Shortened lifespan

  • TDP-43 aggregation, phosphorylation, ubiquitination, and shorter C-terminal species

Transgenic model mice:

  • Expression of TDP-43 or other neurodegenerative disease relevant proteins

  • Adult mice exhibit progressive movement dysfuction, neurodegeneration, shortened lifespan, and accumulation of aggregated, phosphorylated TDP-43

  • Can study events preceding overt symptoms and during the progression of disease

  • Easy to grow and maintain in the laboratory

  • Stable biological and biochemical characteristics

  • Can induce phosphorylation and toxicity of endogenous TDP-43

  • Useful for confirming and characterizing candidate genes or interventions in a mammalian system

  • Cytoplasmic or nuclear aggregates of phosphorylated TDP-43

  • Used to confirm hypotheses of changes in protein expression or protein localization

  • Static, fixed point in the disease course

(A few of the) Big Questions

  • How are TDP-43 post-translational modifications regulated? What are their cellular roles? How are these regulations perturbed in disease?

  • How can we intervene in the development of neurotoxic phosphorylated TDP-43? Can we prevent its accumulation or promote its clearance?

  • How does pathological TDP-43 influence other neurodegenerative diseases when present as a co-pathology?