Neuro-Degeneration
In neurodegenerative conditions, neuronal components and brain function are progressively lost. A spectrum of genes has been implicated in these diseases but mechanistic understanding remains sparse. We have focused on the pathophysiology of Aß in Alzheimer's Disease, and Progranulin in Fronto-Temporal Dementia. In both cases, interaction of extracellular disease-associated ligands with the specific receptors on the neuronal surface is crucial, but had not been defined.
Alzheimer's Disease 
Alzheimer's disease (AD) is the most common cause of age-related dementia, affecting more than 25 million people worldwide. The accumulation of insoluble ß-amyloid (Aß) plaques in the brain has long been considered central to the pathogenesis of AD (green in panel to right). However, recent evidence suggests that soluble oligomeric assemblies of Aß may be of greater importance. APP processing yields Aβ monomers, which undergo oligomerization, eventually forming amyloid fibrils and plaques. Aß oligomers have been found to be potent synaptotoxins, but the mechanism by which they exert their action had remained elusive. We recently found that cellular prion protein (PrP-C) is a high-affinity receptor for Aß oligomers, mediating their toxic effects on synaptic plasticity.
We hypothesize that the Aß/PrP-C interaction leads to dendritic spine retraction via synaptotoxic action, with subsequent neuritic dystrophy and neurodegenerative pathology. These later steps are then coupled to tauopathy and memory impairment in AD. We are employing biochemical analysis, in vivo imaging of dendrites, genetic investigation and behavioral studies to test this hypothesis. With PrP-C as a molecular target, we have launched a drug discovery program for novel AD therapeutics.
Fronto-Temporal Dementia
Of inherited Fronto-Temporal Dementia (FTD) cases, haploinsuffiency of Progranulin is the most common etiology. TDP-43 deposition occurs in Progranulin-deficient FTD, as well as in sporadic FTD cases and in ALS. Because Progranulin is a secreted glycoprotein, we searched for high affinity receptors by expression cloning. We are now characterizing a specific brain protein as a Progranulin receptor. These studies may provide an accessible cell surface approach to modify FTD and ALS progression.
Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. Transgenic mouse models have suggested that endoplasmic reticulum (ER) stress and deficits in ER chaperone function are contributors to ALS pathophysiology. We have shown that NogoA contributes to the proper function of the ER resident chaperone PDI, and is protective against ALS-like neurodegeneration. Our results provide a novel intracellular role for reticulon proteins and support the hypothesis that modulation of PDI function is a potential therapeutic approach to ALS. We are now working to optimize cellular replacement therapy for ALS.