OXPHOS, Pyrimidine Nucleotides, and Alzheimer's Disease: A Pharmacogenomics Approach

Article type: Research Article

Authors: Pesini, Alba^{a; b} | Iglesias, Eldris^{a; b} | Garrido, Nuria^a | Bayona-Bafaluy, M. Pilar^a | Montoya, Julio^{a; b} | Ruiz-Pesini, Eduardo^{a; b; c; *}

Affiliations: [a] Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain | [b] Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Universidad de Zaragoza, Zaragoza, Spain | [c] Fundación ARAID, Universidad de Zaragoza, Zaragoza, Spain

Correspondence: [*] Correspondence to: Eduardo Ruiz-Pesini, Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain. Tel.: +34 976761646; Fax: +34 976761612; E-mail: eduruiz@unizar.es.

Abstract: We present a new hypothesis on the contribution of a dysfunction of the oxidative phosphorylation system, through a decrease in the de novo synthesis of pyrimidine nucleotides, to the pathogenesis of late onset Alzheimer's disease (AD). In the light of this proposition, different treatments for AD patients, such as enhancing the electron flow downstream the coenzyme Q10 of the mitochondrial respiratory chain or increasing mitochondrial biogenesis or directly providing pyrimidines, would be possible. AD is a multifactorial disorder and not all patients would benefit from these treatments. Those healthy individuals harboring mtDNA haplotypes related to a coupled OXPHOS function would probably be the better candidates for these preventive therapies.

Keywords: Alzheimer's disease, coenzyme Q₁₀, de novo pyrimidine biosynthesis, dihydroorotate dehydrogenase, mitochondrial DNA, oxidative phosphorylation

DOI: 10.3233/JAD-140384

Journal: Journal of Alzheimer's Disease, vol. 42, no. 1, pp. 87-96, 2014