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J Alzheimers Dis. 2010;22(2):375-91. doi: 10.3233/JAD-2010-100189.

Protein-DNA interaction at the origin of neurological diseases: a hypothesis.

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  • Departamento de Química Física Aplicada, Universidad Autónoma de Madrid, Centro de Biología Molecular Severo Ochoa, CSIC Madrid, Spain. juans.jimenez@uam.es


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.

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