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

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.

α-Synuclein Induces Alterations in Adult Neurogenesis in Parkinson Disease Models via p53-mediated Repression of Notch1

“…Aberrant protein-DNA interactions mediated by misfolded proteins have been proposed as a novel pathological mechanism common to a myriad of neurological disorders (53). The fact that we did not observed increased levels of p53 in cells accumulating ␣-syn led us to hypothesize that aggravated repression of Notch1 might be a result of the interaction of ␣-syn and p53, which we further demonstrated to occur in adult hippocampal neural progenitors.…”

Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity

“…Because human "amylome" constitutes approximately 15% of all coding polypeptides in the genome, many "self" proteins have the potential to form amyloid (28). Amyloid depositions are frequently heterogeneous containing nonproteinaceous cofactors (15,20,21). Our results suggest that only the type of amyloidcontaining nucleic acids is capable of inducing IFN-I through activating nucleic acid-sensing TLRs.…”

“…Two prototypic amyloidogenic peptides, prion fragment and amyloid β peptide 1-42 (Aβ), bind directly to DNA (19,21). To test whether DNA-containing prion or Aβ fibrils can activate pDCs, we complexed them with oligonucleotide CpG B. CpG B engages TLR9 in the late endosome and induces pDC to produce abundant TNFα and IL-6, but little IFN-I (22).…”

“…Previously, we characterized how misfolded amyloid precursor proteins form amyloid fibrils in the presence of DNA, RNA, and glycosaminoglycans (19). The fibrous aggregates containing nonproteinaceous cofactors displayed the biophysical and biochemical features of amyloids obtained in vitro and from patients, the latter of which are well known to harbor significant amounts of nucleic acids and/or glycosaminoglycans (20,21).…”

Rapid Generation of Amyloid from Native Proteins <em>In vitro</em>

“…We recently established a method to prepare stabilized soluble oligomers of native proteins, which readily form amyloid in the presence of various cofactors 16 . The resulting amyloid fibrils reflect the complex nature of the terminal protein misfolding aggregates 17,18 . Here we use the term protein-only amyloid to refer the protein fibrils without cofactors and hybrid amyloid for the fibrils containing nonproteinaceous components.…”