OVERVIEW

Researchers in our lab are using modern molecular and biochemical methods to identify the mechanisms causing brain degeneration that are most likely to be impacted by new drug therapies.

Using molecular approaches, we are trying to identify and develop potential new drugs for Alzheimer's disease and Krabbe disease.

Work in our laboratory is focused on using modern molecular and biochemical methods to elucidate those pathways involved in neurodegenerative disease that are most amenable to therapeutic intervention.

Work in our laboratory is focused on using modern molecular and biochemical methods to elucidate those pathways involved in neurodegenerative disease that are most amenable to therapeutic intervention.

Using both small molecule libraries and molecular approaches we then seek to identify and develop potential lead therapeutics. Current work in the group is focused on Alzheimer's disease and on Krabbe disease.

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder in the elderly affecting millions of individuals throughout the world. A pathological hallmark of AD is the presence of extracellular protein deposits referred to as senile plaques. The predominant proteinaceous component of these plaques is a self-aggregating peptide known as β amyloid (Aβ).

While not definitive, evidence gathered over the last two decades has implicated Aβ, in particular the longer more amyloidogenic form of the peptide Aβ42, as a potential causative agent in Alzheimer's disease. While considerable effort has been directed at elucidating the enzymes and pathways contributing to the production of Aβ, much less is known regarding Aβ catabolism.

Aβ catabolism is likely to involve proteases at multiple sites, both intracellular and extracellular. Proteases acting at the site of Aβ generation or within the secretory pathway may degrade the peptide intracellularly, thus limiting the amount of the peptide available for secretion.

Cell-surface and secreted proteases may degrade the secreted peptide extracellularly, and endosomal/lysosomal proteases may degrade secreted Aβ following receptor-mediated endocytosis or phagocytosis. Catabolism of Aβ peptides at each of these steps would limit the accumulation of Aβ, and disruption of this catabolism may be a risk factor for AD.

Using pharmacological, molecular and biochemical approaches, our laboratory has recently identified the endothelin-converting enzymes (ECEs) as novel Aβ-degrading enzymes. Overexpression of ECE-1 in cells that lack endogenous ECE activity results in a pronounced decrease in Aβ accumulation in the conditioned media. In addition, partially purified recombinant ECE can directly degrade Aβ in vitro with a favorable kinetic profile.

We are currently evaluating the role of ECE and other reported Aβ degrading enzymes using transgenic and knockout approaches as well as further examining the role of these enzymes in AD. In addition, our group is using high throughput cell-based screens to identify compounds that are capable of influencing Aβ accumulation. These compounds can be used to investigate the factors contributing to Aβ accumulation and may provide novel leads for drug discovery. Using these approaches we have already identified several compounds capable of influencing Aβ accumulation, including one that selectively reduces Aβ ending at position Aβ42.

Krabbe disease is a degenerative neurological disorder primarily affecting infants and young children, although rare cases of adult onset have been described. Affected individuals typically present with symptoms in the first few months of life. Disease progression is generally rapid, leading to death within 1 to 2 years.

Pathologically, the brains of affected individuals are characterized by a severe loss of oligodendrocytes and myelin and the appearance of mono and multinucleated macrophages with a classical globoid appearance. The disease is inherited as an autosomal recessive trait caused by mutations in the galactocerebrosidase (GALC) gene that significantly reduce the activity of the enzyme.

An obvious therapeutic approach for the treatment of Krabbe disease is to restore GALC enzymatic activity in the brain. We are currently exploring several methods to accomplish this goal including protein transduction techniques.