Protein-DNA Interaction at the Origin of Neurological Diseases: A Hypothesis

Article type: Review Article

Authors: Jiménez, Juan S.^{; *}

Affiliations: Departamento de Química Física Aplicada, Universidad Autónoma de Madrid, Centro de Biología Molecular Severo Ochoa, CSIC Madrid, Spain

Correspondence: [*] Correspondence to: Juan S. Jiménez, Departamento de Química Física Aplicada, Universidad Autónoma de Madrid, Centro de Biología Molecular Severo Ochoa, CSIC 28049 Madrid, Spain. Tel.: +34 914974724; Fax: +34 914974785; Email: [email protected].

Abstract: A number of neurodegenerative diseases, including Alzheimer's disease, tauopathies, Parkinson's disease, and synucleinopathies, polyglutamine diseases, including Huntington's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy, are characterized by the existence of a protein or peptide prone to aggregation specific to the disease: amyloid-β, tau protein, α-synuclein, atrophin 1, androgen receptor, prion protein, copper-zinc superoxide dismutase, α 1A subunit of CaV2.1, TATA-box binding protein, huntingtin, and ataxins 1, 2, 3, and 7. Beside this common molecular feature, we have found three additional main properties related to the disease-connected protein or peptide, which are shared by all those neurological disorders: first, proneness to aggregation, which, in many cases, seems to be bound to the lack of a clearly defined secondary structure; second, reported presence of the disease-related protein inside the nucleus; and finally, an apparently unspecific interaction with DNA. These findings, together with the lack of clear details to explain the molecular origin of these neurodegenerative diseases, invite a hypothesis that, together with other plausible molecular explanations, may contribute to find the molecular basis of these diseases: I propose here the hypothesis that many neurological disorders may be the consequence, at least in part, of an aberrant interaction of the disease-related protein with nucleic acids, therefore affecting the normal DNA expression and giving place to a genetic stress which, in turn, alters the expression of proteins needed for the normal cellular function and regulation.

Keywords: Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, polyglutamine diseases, transmissible spongiform encephalopathy

DOI: 10.3233/JAD-2010-100189

Journal: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 375-391, 2010