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Oscillations in Neuronal Activity: A Neuron-Centered Spatiotemporal Model of the Unfolded Protein Response in Prion Diseases.
Miller, Elliot M; Chan, Tat Chung D; Montes-Matamoros, Carlos; Sharif, Omar; Pujo-Menjouet, Laurent; Lindstrom, Michael R.
Afiliación
  • Miller EM; College of Arts and Sciences, Culverhouse College of Business, The University of Alabama, Tuscaloosa, AL, USA.
  • Chan TCD; Department of Mathematics, University of California Berkeley, Berkeley, CA, USA.
  • Montes-Matamoros C; School of Mathematical and Statistical Sciences, The University of Texas Rio Grande Valley, Edinburg, TX, USA.
  • Sharif O; School of Mathematical and Statistical Sciences, The University of Texas Rio Grande Valley, Edinburg, TX, USA.
  • Pujo-Menjouet L; Universite Claude Bernard Lyon 1, CNRS, Ecole Centrale de Lyon, INSA Lyon, Université Jean Monnet, ICJ UMR5208, Inria, 69622, Villeurbanne, France.
  • Lindstrom MR; School of Mathematical and Statistical Sciences, The University of Texas Rio Grande Valley, Edinburg, TX, USA. mike.lindstrom@utrgv.edu.
Bull Math Biol ; 86(7): 82, 2024 Jun 05.
Article en En | MEDLINE | ID: mdl-38837083
ABSTRACT
Many neurodegenerative diseases (NDs) are characterized by the slow spatial spread of toxic protein species in the brain. The toxic proteins can induce neuronal stress, triggering the Unfolded Protein Response (UPR), which slows or stops protein translation and can indirectly reduce the toxic load. However, the UPR may also trigger processes leading to apoptotic cell death and the UPR is implicated in the progression of several NDs. In this paper, we develop a novel mathematical model to describe the spatiotemporal dynamics of the UPR mechanism for prion diseases. Our model is centered around a single neuron, with representative proteins P (healthy) and S (toxic) interacting with heterodimer dynamics (S interacts with P to form two S's). The model takes the form of a coupled system of nonlinear reaction-diffusion equations with a delayed, nonlinear flux for P (delay from the UPR). Through the delay, we find parameter regimes that exhibit oscillations in the P- and S-protein levels. We find that oscillations are more pronounced when the S-clearance rate and S-diffusivity are small in comparison to the P-clearance rate and P-diffusivity, respectively. The oscillations become more pronounced as delays in initiating the UPR increase. We also consider quasi-realistic clinical parameters to understand how possible drug therapies can alter the course of a prion disease. We find that decreasing the production of P, decreasing the recruitment rate, increasing the diffusivity of S, increasing the UPR S-threshold, and increasing the S clearance rate appear to be the most powerful modifications to reduce the mean UPR intensity and potentially moderate the disease progression.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades por Prión / Conceptos Matemáticos / Respuesta de Proteína Desplegada / Modelos Neurológicos / Neuronas Límite: Animals / Humans Idioma: En Revista: Bull Math Biol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedades por Prión / Conceptos Matemáticos / Respuesta de Proteína Desplegada / Modelos Neurológicos / Neuronas Límite: Animals / Humans Idioma: En Revista: Bull Math Biol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos