Our studies address a major need in society. The aging population faces increased incidence of late-age-onset neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Currently, we do not have a cure or any effective treatment to slow disease progression. Understanding the pathogenic mechanisms and developing effective prophylactic, diagnostic and therapeutic strategies are urgently needed.
Although late-age-onset neurodegenerative diseases have varying clinical manifestations, they share a common thread — specifically, they all involve the deposition of protein aggregates in the central nervous system. The correlation of these protein aggregates with disease is well established by extensive pathological studies, but exactly how these aggregates cause neurodegeneration remains obscure. Our studies seek to find answers, specifically in Parkinson’s disease and prion disease.
Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by the aggregation of abnormal alpha-synuclein (a-syn) proteins. We investigate the role of a-syn in PD using a multifaceted approach.
First, we are developing an in vitro a-syn seeding assay with recombinant a-syn to determine if the seeding activity of aggregates can be a reliable biomarker for PD.
Second, taking advantage of the seeding activity of preformed a-syn amyloid fibrils, we have developed a-syn aggregation models in primary neurons, organotypic brain slice cultures and rodents. Using these models, we are studying the pathogenic mechanisms of PD with a special emphasis on the initial molecular and cellular changes induced by misfolded a-syn.
Third, we are developing novel reagents that specifically react with various types of a-syn aggregates, which will enable us to elucidate its neurotoxic mechanisms and which have utility as novel tools with great diagnostic or therapeutic potential.
Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a unique group of neurodegenerative disorders that includes Creutzfeldt-Jakob disease in humans, mad cow disease in cattle, scrapie in sheep and chronic wasting disease in deer and elk. In addition to sporadic and inherited forms, TSEs are bona fide infectious diseases. The infectious agents of TSEs are a prions, misfolded forms of the host’s normal prion proteins (PrP) that aggregate in the brain.
Our lab has established a platform to generate highly infectious prions with recombinant PrP plus cofactors in the test tube. Using this system, we study the features of PrP aggregates that are essential for the prion’s infectivity and are developing strategies to detect and neutralize them. These studies also will shed light on the pathogenic mechanisms of other neurodegenerative disorders.