Defining reaction mechanisms of threshold phenomena in conformational disease

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DESCRIPTION (provided by applicant): Diseases involving disruptions in proper protein folding are termed "conformational diseases." Proteins undergo misfolding due to mutation, stress or stochastic events. Misfolded proteins form aggregates and impact native (bystander) protein form and function. These disruptions to protein homeostasis are well known to be associated with neurological and prion diseases. Less known, however is the association between protein misfolding and certain diabetic phenotypes. The mechanisms of the impact of protein misfolding and aggregation on native protein formation and production are not well understood. One often observed occurrence in conformational diseases is a threshold phenomenon. Cellular aggregate levels are somehow driven across a threshold from nontoxic to toxic. Our long range goal is to elucidate the mechanism(s) of the impact of aggregate prone misfolded protein on bystander protein development. Our immediate goal is to further describe the conditions necessary for the threshold phenomenon observed in conformational diseases. Here, we present preliminary data of a general mathematical model describing the impact of misfolded protein on bystander protein production and the conditions for existence of a threshold phenomenon. Two aims will examine how the threshold phenomenon manifests in conformational diseases: Specific Aim 1: Identify the key reaction motifs responsible for the manifestation of threshold phenomena in conformational diseases. Specific Aim 2: Evaluate the effects of protein fluxes on the dynamical behavior of native protein disappearance in conformational diseases. PUBLIC HEALTH RELEVANCE: A disruption in cellular quality control processes can lead to the mismanagement of misfolded proteins, resulting in toxic protein aggregation and disease. Elevated levels of misfolded protein and associated aggregation are implicated in a variety of diseases such as Alzheimer's, Charcot-Marie-Tooth and diabetes mellitus. Understanding the detailed mechanisms behind protein misfolding and aggregation will lend insight into cellular quality control as well as into potential treatments for patients with protein misfolding diseases.