What we do

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.

Model systems are powerful tools to explore the underlying biology of TDP-43 proteinopathies and to develop new therapeutic strategies.  We employ C. elegans, cell culture, and mouse models, as well as human post-mortem tissue.

• 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?