Abstract
Previously, we hypothesized that an RNA-based pathogenic pathway has a causal role in the dominantly inherited unstable expanded repeat neurodegenerative diseases. In support of this hypothesis we, and others, have characterized rCAG.rCUG100 repeat double-strand RNA (dsRNA) as a previously unidentified agent capable of causing pathogenesis in a Drosophila model of neurodegenerative disease. Dicer, Toll, and autophagy pathways have distinct roles in this Drosophila dsRNA pathology. Dicer dependence is accompanied by cleavage of rCAG.rCUG100 repeat dsRNA down to r(CAG)7 21-mers. Among the “molecular hallmarks” of this pathway that have been identified in Drosophila, some [i.e., r(CAG)7 and elevated tumor necrosis factor] correlate with observations in affected people (e.g., Huntington’s disease and amyotrophic lateral sclerosis) or in related animal models (i.e., autophagy). The Toll pathway is activated in the presence of repeat-containing dsRNA and toxicity is also dependent on this pathway. How might the endogenously expressed dsRNA mediate Toll-dependent toxicity in neuronal cells? Endogenous RNAs are normally shielded from Toll pathway activation as part of the mechanism to distinguish “self” from “non-self” RNAs. This typically involves post-transcriptional modification of the RNA. Therefore, it is likely that rCAG.rCUG100 repeat dsRNA has a characteristic property that interferes with or evades this normal mechanism of shielding. We predict that repeat expansion leads to an alteration in RNA structure and/or form that perturbs RNA modification, causing the unshielded repeat RNA (in the form of its Dicer-cleaved products) to be recognized by Toll-like receptors (TLRs), with consequent activation of the Toll pathway leading to loss of cell function and then ultimately cell death. We hypothesize that the proximal cause of expanded repeat neurodegenerative diseases is the TLR recognition (and resultant innate inflammatory response) of repeat RNA as “non-self” due to their paucity of “self” modification.
Highlights
Since the first discovery of trinucleotide repeat expansion as the basis for many important human genetic diseases (Kremer et al, 1991; La Spada et al, 1991; Yu et al, 1991; Richards and Sutherland, 1992), there has been a vast amount of research in this area (PubMed search “trinucleotide repeat disorders” gives >3,700 results)
The disease, appears to be due to defects in the processes that remove and/or modify endogenous nucleic acids. These endogenous unmodified nucleic acids accumulate and are sensed as “non-self ” by Toll -like receptors (TLRs), that, in turn, activate innate inflammatory regulatory pathways. This bears a striking resemblance to mechanisms we have identified as responsible for double-strand RNA (dsRNA) pathogenesis in the Drosophila model of expanded repeat neurodegenerative diseases
A growing body of literature indicates a consistent association between innate immunity, neuroinflammation and neurodegeneration (Shastri et al, 2013)
Summary
Since the first discovery of trinucleotide repeat expansion as the basis for many important human genetic diseases (Kremer et al, 1991; La Spada et al, 1991; Yu et al, 1991; Richards and Sutherland, 1992), there has been a vast amount of research in this area (PubMed search “trinucleotide repeat disorders” gives >3,700 results). For at-risk individuals in families affected with dominantly inherited late-onset neurodegenerative diseases due to expanded repeats, the majority opt not to have the definitive pre-symptomatic diagnostic test. Their preference is to live with the uncertainty of not knowing, than the certainty of getting the disease, as no treatments are yet available. Determining the pathogenic pathway and identifying therapeutic targets for intervention is an urgent priority for reducing the impact of these devastating diseases. This understanding is essential for rational approaches to delay onset, slow progression, or effect cure
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