Molecular Mechanisms of Peripheral Prion Pathogenesis

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DESCRIPTION (provided by applicant): Prion diseases affect numerous species including humans, but a cure for these invariably fatal, neurodegenerative diseases is currently lacking. The ideology of the proposed research involves understanding how prions spread and propagate before they reach the brain where they inflict neurodegeneration and subsequent death. Although the immune system normally aids in clearing the body of infections, prions counter-intuitively utilize a specific part of the immune system termed Complement to spread to sites of replication. Specifically, if you genetically manipulate mice to lack certain Complement proteins, the animals either resist disease entirely or exhibit a delayed disease onset. The immune system consists of two main branches: the first line of defense, termed innate immunity, and a slower yet more specific branch termed adaptive immunity. Complement plays a role in the body's first line of defense against an infectious agent mainly through recognizing patterns common to pathogens yet absent on host cells. Considering prions use Complement to spread disease, one of the aims within involves characterizing the interaction between naturally derived prions and Complement proteins through surface plasmon resonance, a broadly used technology used for studying molecular interactions. Identifying the Complement proteins which directly bind proteins with the greatest strength could provide therapeutic targets for preventing disease progression. Factor H inhibits Complement recognition of host tissues and thus plays a role in preventing autoimmunity. Others have shown Factor H binds both normally folded as well as misfolded prion protein. These findings raise the question of whether Factor H plays a role in limiting the spread of prions through preventing Complement recognition. The second aim described within will test the hypothesis that Factor H prevents prion disease by binding prions and inhibiting Complement recognition. If Factor H indeed plays this role in prion disease, then mice deficient in Factor H will succumb to prion disease at a faster rate than Factor H sufficient mice. If so, then perhaps overexpression or treatment with Factor H could serve to limit disease progression. Ultimately, the proposed projects parallel the NINDS mission through the shared goal of understanding causes and progression of neurological diseases with the ultimate goal to provide potential therapeutic targets for a cure.