We are currently developing new therapeutic strategies to treat neurodegenerative diseases such as Alzheimers and Frontal Temporal Dementia (FTD).

Progranulin and TDP-43

Understanding the Role of Progranulin and TDP-43 in Neurodegneration

The aggregation and deposition of ubiquitinated and misfolded proteins in neuronal and glial cells of the central nervous system (CNS) is increasingly recognized as a characteristic feature of common neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)4. Mutations in the gene encoding the secreted growth factor progranulin (PGRN) have been identified as a major cause of familial frontotemporal lobar degeneration (FTLD) with ubiquitin and TDP-43-positive inclusions5,6. Interestingly, mutations in the gene encoding TDP-43 (TARDBP) have also been identified as a direct cause of neurodegeneration in sporadic and familial patients with amyotrophic lateral sclerosis7,8. The link between reduced levels of PGRN and aggregation of TDP-43 is unclear. Our laboratory is using multiple strategies to investigate the biochemical ink between these two proteins to, decipher the mechanism of neurodegneration in FTD and ALS, and identify new drug targets and ultimately therapies that are desperately needed for these disorders. .

Gamma-Secretase Modulators

Substrate-Targeting γ-Secretase Modulators as Alzheimer's disease therapies.

Alzheimer's disease (AD) is the most prevalent and costly form of dementia in the world, with no truly effective treatment. Approximately 5 million Americans are suffering from Alzheimer's disease (AD) and this number is projected to grow to 14 million by 2050, costing the US over an estimated 1 trillion dollars 1. New, effective therapies that can treat or prevent the progression of AD are desperately needed. The preponderance of evidence supports the hypothesis that accumulation of the amyloid β (Aβ) peptide in the brain causes AD. Specifically a 42 amino acid isoform of Aβ (Aβ42) is aggregation prone, toxic, and thought to initiate AD dementia2. We have recently discovered a group of compounds, called substrate-targeting γ-secretase modulators (stGSMs) that circumvent problems associated with some therapeutic approaches being pursued by other drug discovery programs3. stGSMs not only potently inhibit Aβ42 they also inhibit the aggregation of Aβ42 by directly binding to the peptide. Based on our data stGSMs are excellent AD drug leads to test the hypothesis that selective reduction of Aβ42 levels and aggregation will prevent and/or stop the Alzheimer's disease neurodegeneration and cognitive decline. Our laboratory is investigating the mechanism of GSMs, testing their in vivo efficacy, and working to improve their potency and pharmacological properties.


1. 2010 Alzheimer's disease facts and figures. Alzheimer's and Dementia 6, 158-194, (2010).

2. Hardy, J. & Selkoe, D. J. The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics. Science 297, 353-356 (2002).

3. Kukar, T. L. et al. Substrate-targeting gamma-secretase modulators. Nature 453, 925-929, (2008).

4. Taylor, J. P., Hardy, J. & Fischbeck, K. H. Toxic proteins in neurodegenerative disease. Science 296, 1991-5 (2002).

5. Baker, M. et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916-9 (2006).

6. Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130-3 (2006).

7. Kabashi, E. et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet (2008).

8. Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668-72 (2008).