Protein-Encoding RNA-to-RNA Information Transfer in Mammalian Cells: Principles of RNA-Dependent mRNA Amplification

Volloch, Vladimir

doi:10.33597/aimm.01-1002

Cited by 11 publications

(68 citation statements)

References 72 publications

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“…Moreover, observations of widespread synthesis of antisense RNA initiating at the 3'poly(A) of mRNAs in human cells [46] suggested an extensive cellular utilization of mammalian RdRp activity. These results led to the development of a model of RdRpfacilitated and antisense RNA-mediated amplification of mammalian mRNA [47][48][49]. Recent detection of the major model-predicted identifiers, chimeric RNA intermediates containing both sense and antisense RNA strands covalently joined in a rigorously predicted and uniquely defined manner [49,50], as well as the identification of a putative chimeric RNA end product of this process [49], validated the proposed model.…”

Section: "Chimeric" Pathway Of Mammalian Rna-dependent Mrna Amplificationmentioning

confidence: 93%

“…Since it is presumably βAPP-and beta-secretase-independent, the N-terminus of the resulting polypeptide should be absolutely precisely that of Aβ (it can be longer than Aβ at its C-end and be trimmed to size by gamma-secretase cleavage). This is an exceedingly tall order yet, as described below, it can be accomplished by a process known as "chimeric RNA-dependent mammalian mRNA amplification" [34,48,49].…”

Section: Asymmetric Amplification Of βApp Mrna Leading To Generation Of C99 Fragment Of βAppmentioning

confidence: 99%

“…The process of RNA-dependent amplification of mammalian mRNA is described in detail elsewhere [48,49]. Here, it is diagrammed in Figure 1 below and can be briefly summarized as follows.…”

Section: "Chimeric" Pathway Of Mammalian Rna-dependent Mrna Amplificationmentioning

confidence: 99%

“…Here, it is diagrammed in Figure 1 below and can be briefly summarized as follows. The amplification process occurs in the cytoplasm and starts with transcription of the antisense complement from a conventional spliced mRNA template, initiating at the 3'poly(A), possibly with the help of a uridilated protein, as seen in viral RdRs [51] (Figure 1, Step 1), and terminating at the 3' end with the "C", a transcript of the capG of mRNA [48][49][50]. Generation of a complete antisense transcript requires the presence of an eligible RNA template and a compatible polymerase activity.…”

Section: "Chimeric" Pathway Of Mammalian Rna-dependent Mrna Amplificationmentioning

confidence: 99%

“…Generation of a complete antisense transcript requires the presence of an eligible RNA template and a compatible polymerase activity. The only major prerequisite for a potential RNA template appears to be the presence of the poly(A) segment at its 3' terminus [46][47][48][49]. The compatible polymerase activity is RdRp.…”

Section: "Chimeric" Pathway Of Mammalian Rna-dependent Mrna Amplificationmentioning

confidence: 99%

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AD “Statin”: Alzheimer’s Disorder is a “Fast” Disease Preventable by Therapeutic Intervention Initiated Even Late in Life and Reversible at the Early Stages

Volloch¹,

Br²,

Rits³

2019

AIMM

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The present study posits that Alzheimer's disorder is a "fast" disease. This is in sharp contrast to a view, prevailing until now, that Alzheimer's Disease (AD) is a quintessential "slow" disease that develops throughout the life as one prolonged process. According to this view, beta-amyloid (Aβ) is produced solely by the beta-amyloid precursor protein (βAPP) proteolytic pathway. As its levels increase, it triggers neurodegeneration starting relatively early in life. Damages accumulate and manifest, late in life in sporadic Alzheimer's Disease (SAD) cases, as AD symptoms. In familial AD (FAD) cases, where mutations in βAPP gene or in presenilins increase production of either common Aβ isoform or of its more toxic isoforms, neurodegeneration reaches critical threshold sooner and AD symptoms occur earlier in life, mostly in late 40s and 50s. There are currently no preventive AD therapies but if they were available, according to this viewpoint it would be largely futile to intervene late in life in case of potential SAD or at mid-age in cases of FAD because, although AD symptoms have not yet manifested, the damage has already occurred during the preceding decades. In this paradigm, to be effective, preventive therapeutic intervention should be initiated early in life. The outlook suggested by the present study is radically different. According to it, Alzheimer's disease evolves in two stages. The first stage is a slow process of beta-amyloid accumulation. It occurs via βAPP proteolytic pathway common to Homo sapiens, including healthy humans, and to non-human mammals, and results neither in significant damage, nor in manifestation of the disease. The second stage occurs exclusively in humans, commences shortly before symptomatic onset of the disease, sharply accelerates the production of Aβ, generates significant damages, triggers AD symptoms, and is fast. It is driven by an Aβ generation pathway qualitatively and quantitatively different from βAPP proteolytic process and entirely independent of beta-amyloid precursor protein, and results in rapid and substantial accumulation of Aβ, consequent significant neurodegeneration, and symptomatic AD. In this paradigm, a preventive therapy for AD, an AD "statin", would be effective when initiated at any time prior to commencement of the second stage. Moreover, there are good reasons to believe that with a drug blocking βAPP-independent Aβ production pathway in the second stage, it would be possible not only to preempt the disease but also to stop and to reverse it even when early AD symptoms have already manifested. The present study posits a notion of AD as a Fast Disease, offers evidence for the occurrence of the ADspecific Aβ production pathway, describes cellular and molecular processes constituting an engine that drives Alzheimer's disease, and explains why non-human mammals are not susceptible to AD and why only a subset of humans develop the disease. It establishes that Alzheimer's disease is preventable by therapeutic intervention initiated even late in life, detail...

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Section: "Chimeric" Pathway Of Mammalian Rna-dependent Mrna Amplificationmentioning

confidence: 93%

Section: Asymmetric Amplification Of βApp Mrna Leading To Generation Of C99 Fragment Of βAppmentioning

confidence: 99%

“…The process of RNA-dependent amplification of mammalian mRNA is described in detail elsewhere [48,49]. Here, it is diagrammed in Figure 1 below and can be briefly summarized as follows.…”

Section: "Chimeric" Pathway Of Mammalian Rna-dependent Mrna Amplificationmentioning

confidence: 99%

Section: "Chimeric" Pathway Of Mammalian Rna-dependent Mrna Amplificationmentioning

confidence: 99%

Section: "Chimeric" Pathway Of Mammalian Rna-dependent Mrna Amplificationmentioning

confidence: 99%

See 3 more Smart Citations

AD “Statin”: Alzheimer’s Disorder is a “Fast” Disease Preventable by Therapeutic Intervention Initiated Even Late in Life and Reversible at the Early Stages

Volloch¹,

Br²,

Rits³

2019

AIMM

Self Cite

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The Amyloid Cascade Hypothesis 2.0: On the Possibility of Once-in-a-Lifetime-Only Treatment for Prevention of Alzheimer’s Disease and for Its Potential Cure at Symptomatic Stages

Volloch

Rits-Volloch

2022

ADR

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We posit that Alzheimer’s disease (AD) is driven by amyloid-β (Aβ) generated in the amyloid-β protein precursor (AβPP) independent pathway activated by AβPP-derived Aβ accumulated intraneuronally in a life-long process. This interpretation constitutes the Amyloid Cascade Hypothesis 2.0 (ACH2.0). It defines a tandem intraneuronal-Aβ (iAβ)-anchored cascade occurrence: intraneuronally-accumulated, AβPP-derived iAβ triggers relatively benign cascade that activates the AβPP-independent iAβ-generating pathway, which, in turn, initiates the second, devastating cascade that includes tau pathology and leads to neuronal loss. The entire output of the AβPP-independent iAβ-generating pathway is retained intraneuronally and perpetuates the pathway’s operation. This process constitutes a self-propagating, autonomous engine that drives AD and ultimately kills its host cells. Once activated, the AD Engine is self-reliant and independent from Aβ production in the AβPP proteolytic pathway; operation of the former renders the latter irrelevant to the progression of AD and brands its manipulation for therapeutic purposes, such as BACE (beta-site AβPP-cleaving enzyme) inhibition, as futile. In the proposed AD paradigm, the only valid direct therapeutic strategy is targeting the engine’s components, and the most effective feasible approach appears to be the activation of BACE1 and/or of its homolog BACE2, with the aim of exploiting their Aβ-cleaving activities. Such treatment would collapse the iAβ population and ‘reset’ its levels below those required for the operation of the AD Engine. Any sufficiently selective iAβ-depleting treatment would be equally effective. Remarkably, this approach opens the possibility of a short-duration, once-in-a-lifetime-only or very infrequent, preventive or curative therapy for AD; this therapy would be also effective for prevention and treatment of the ‘common’ pervasive aging-associated cognitive decline. The ACH2.0 clarifies all ACH-unresolved inconsistencies, explains the widespread ‘resilience to AD’ phenomenon, predicts occurrences of a category of AD-afflicted individuals without excessive Aβ plaque load and of a novel type of familial insusceptibility to AD; it also predicts the lifespan-dependent inevitability of AD in humans if untreated preventively. The article details strategy and methodology to generate an adequate AD model and validate the hypothesis; the proposed AD model may also serve as a research and drug development platform.

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The Amyloid Cascade Hypothesis 2.0: Generalization of the Concept

Volloch

Rits-Volloch

2023

ADR

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Recently, we proposed the Amyloid Cascade Hypothesis 2.0 (ACH2.0), a reformulation of the ACH. In the former, in contrast to the latter, Alzheimer’s disease (AD) is driven by intraneuronal amyloid-β (iAβ) and occurs in two stages. In the first, relatively benign stage, Aβ protein precursor (AβPP)-derived iAβ activates, upon reaching a critical threshold, the AβPP-independent iAβ-generating pathway, triggering a devastating second stage resulting in neuronal death. While the ACH2.0 remains aligned with the ACH premise that Aβ is toxic, the toxicity is exerted because of intra- rather than extracellular Aβ. In this framework, a once-in-a-lifetime-only iAβ depletion treatment via transient activation of BACE1 and/or BACE2 (exploiting their Aβ-cleaving activities) or by any means appears to be the best therapeutic strategy for AD. Whereas the notion of differentially derived iAβ being the principal moving force at both AD stages is both plausible and elegant, a possibility remains that the second AD stage is enabled by an AβPP-derived iAβ-activated self-sustaining mechanism producing a yet undefined deleterious “substance X” (sX) which anchors the second AD stage. The present study generalizes the ACH2.0 by incorporating this possibility and shows that, in this scenario, the iAβ depletion therapy may be ineffective at symptomatic AD stages but fully retains its preventive potential for both AD and the aging-associated cognitive decline, which is defined in the ACH2.0 framework as the extended first stage of AD.

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Protein-Encoding RNA-to-RNA Information Transfer in Mammalian Cells: Principles of RNA-Dependent mRNA Amplification

Cited by 11 publications

References 72 publications

AD “Statin”: Alzheimer’s Disorder is a “Fast” Disease Preventable by Therapeutic Intervention Initiated Even Late in Life and Reversible at the Early Stages

AD “Statin”: Alzheimer’s Disorder is a “Fast” Disease Preventable by Therapeutic Intervention Initiated Even Late in Life and Reversible at the Early Stages

The Amyloid Cascade Hypothesis 2.0: On the Possibility of Once-in-a-Lifetime-Only Treatment for Prevention of Alzheimer’s Disease and for Its Potential Cure at Symptomatic Stages

The Amyloid Cascade Hypothesis 2.0: Generalization of the Concept

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