Physiological and Pathological Role of Alpha-synuclein in Parkinson’s Disease Through Iron Mediated Oxidative Stress; The Role of a Putative Iron-responsive Element

Olivares, David; Huang, Xudong; Branden, Lars; Greig, Nigel H.; Rogers, Jack T.

doi:10.3390/ijms10031226

Cited by 75 publications

(77 citation statements)

References 199 publications

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“…We also studied the ability of FMRP and TDP-43 to regulate their own expression levels through autogenous interactions, characterizing their binding sites in great detail (Schaeffer et al 2001;Ayala et al 2011). We analyzed the interaction between IRP-1 and APP (Cho et al 2010) and predicted the interaction between IRP-1 and an IRE-like region of α-synuclein mRNA, which represents a link to the iron-pathway deregulation associated with PD (Olivares et al 2009). Finally, we investigated the ability of RNA aptamers to bind to aggregation-prone regions of prions (Proske et al 2002), which shows that our theoretical framework could be useful for the in silico screening of RNA-based therapeuticals (Table 1).…”

Section: Discussionmentioning

confidence: 99%

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Neurodegenerative diseases: Quantitative predictions of protein–RNA interactions

Cirillo

Federico

Klus

et al. 2012

RNA

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Increasing evidence indicates that RNA plays an active role in a number of neurodegenerative diseases. We recently introduced a theoretical framework, catRAPID, to predict the binding ability of protein and RNA molecules. Here, we use catRAPID to investigate ribonucleoprotein interactions linked to inherited intellectual disability, amyotrophic lateral sclerosis, Creutzfeuld-Jakob, Alzheimer's, and Parkinson's diseases. We specifically focus on (1) RNA interactions with fragile X mental retardation protein FMRP; (2) protein sequestration caused by CGG repeats; (3) noncoding transcripts regulated by TAR DNA-binding protein 43 TDP-43; (4) autogenous regulation of TDP-43 and FMRP; (5) iron-mediated expression of amyloid precursor protein APP and α-synuclein; (6) interactions between prions and RNA aptamers. Our results are in striking agreement with experimental evidence and provide new insights in processes associated with neuronal function and misfunction.

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Section: Discussionmentioning

confidence: 99%

“…7; Olivares et al 2009). According to our calculations, the IRE-containing fragment of α-synuclein mRNA (nucleotides 190-252) has the highest propensity to bind to IRP-1 ( Fig.…”

Section: Iron-mediated Expression Of App and α-Synucleinmentioning

confidence: 99%

Neurodegenerative diseases: Quantitative predictions of protein–RNA interactions

Cirillo

Federico

Klus

et al. 2012

RNA

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“…Evidence from studies on inherited disorders of iron metabolism indicates that neurodegeneration occurs with iron accumulation (Mills et al, 2010). Olivares et al, (2009) reported that iron accumulation is probably a primary event and not a consequence of degenerative diseases. In a rat model, when FeCl 3 was injected into the substantia nigra, there was selective decrease in striatal dopamine suggesting that iron is responsible for dopaminergic neurodegeneration.…”

Section: Iron Ros and Neurodegenerationmentioning

confidence: 99%

“…In mice, deletion of the gene encoding for IRP2 which interferes with regulation of iron metabolism has been found to result in abnormal iron deposition in the brain, as well as ataxia, tremors and neurodegeneration. Similarly mutation in the gene coding for a ferritin subunit and polymorphisms in genes related to iron homeostasis have been associated with iron deposits, neuronal degradation and sometimes PD (Olivares et al, 2009). …”

Section: Iron Ros and Neurodegenerationmentioning

confidence: 99%

“…Neuromelanin sequesters redox ions that have affinity for ferric ions. If it is bound to an excess of ferric ions, neuromelanin functions like a prooxidant, reduces the ferric to ferrous and increases the amount of iron available to react with H 2 O 2 (Olivares et al, 2009). Iron not only induces oxidative stress but damages proteins, membranes, and nucleic acids and eventually leads dopaminergic neuron death in the substantia nigra (Logroscino et al, 2008).…”

Section: Parkinson's Diseasementioning

confidence: 99%

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Iron, Oxidative Stress and Health

Udipi¹,

Ghugre²,

Gokhale³

2012

Oxidative Stress - Molecular Mechanisms and Biological Effects

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Targeting increased levels of APP in Down syndrome: Posiphen‐mediated reductions in APP and its products reverse endosomal phenotypes in the Ts65Dn mouse model

Chen

Salehi

Pearn

et al. 2020

Alzheimer's & Dementia

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Objective Recent clinical trials targeting amyloid beta (Aβ) and tau in Alzheimer's disease (AD) have yet to demonstrate efficacy. Reviewing the hypotheses for AD pathogenesis and defining possible links between them may enhance insights into both upstream initiating events and downstream mechanisms, thereby promoting discovery of novel treatments. Evidence that in Down syndrome (DS), a population markedly predisposed to develop early onset AD, increased APP gene dose is necessary for both AD neuropathology and dementia points to normalization of the levels of the amyloid precursor protein (APP) and its products as a route to further define AD pathogenesis and discovering novel treatments. Background AD and DS share several characteristic manifestations. DS is caused by trisomy of whole or part of chromosome 21; this chromosome contains about 233 protein‐coding genes, including APP. Recent evidence points to a defining role for increased expression of the gene for APP and for its 99 amino acid C‐terminal fragment (C99, also known as β‐CTF) in dysregulating the endosomal/lysosomal system. The latter is critical for normal cellular function and in neurons for transmitting neurotrophic signals. New/updated hypothesis We hypothesize that the increase in APP gene dose in DS initiates a process in which increased levels of full‐length APP (fl‐APP) and its products, including β‐CTF and possibly Aβ peptides (Aβ42 and Aβ40), drive AD pathogenesis through an endosome‐dependent mechanism(s), which compromises transport of neurotrophic signals. To test this hypothesis, we carried out studies in the Ts65Dn mouse model of DS and examined the effects of Posiphen, an orally available small molecule shown in prior studies to reduce fl‐APP. In vitro, Posiphen lowered fl‐APP and its C‐terminal fragments, reversed Rab5 hyperactivation and early endosome enlargement, and restored retrograde transport of neurotrophin signaling. In vivo, Posiphen treatment (50 mg/kg/d, 26 days, intraperitoneal [i.p.]) of Ts65Dn mice was well tolerated and demonstrated no adverse effects in behavior. Treatment resulted in normalization of the levels of fl‐APP, C‐terminal fragments and small reductions in Aβ species, restoration to normal levels of Rab5 activity, reduced phosphorylated tau (p‐tau), and reversed deficits in TrkB (tropomyosin receptor kinase B) activation and in the Akt (protein kinase B [PKB]), ERK (extracellular signal‐regulated kinase), and CREB (cAMP response element–binding protein) signaling pathways. Remarkably, Posiphen treatment also restored the level of choline acetyltransferase protein to 2N levels. These findings support the APP gene dose hypothesis, point to the need for additional studies to explore the mechanisms by which increased APP gene expression acts to increase the risk for AD in DS, and to possible utility of treatments to normalize the levels of APP and its products for preventing AD in those with DS. Major challenges for the hypothesis Important unanswered questions are: (1) When should one intervene in t...

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Physiological and Pathological Role of Alpha-synuclein in Parkinson’s Disease Through Iron Mediated Oxidative Stress; The Role of a Putative Iron-responsive Element

Cited by 75 publications

References 199 publications

Neurodegenerative diseases: Quantitative predictions of protein–RNA interactions

Neurodegenerative diseases: Quantitative predictions of protein–RNA interactions

Iron, Oxidative Stress and Health

Targeting increased levels of APP in Down syndrome: Posiphen‐mediated reductions in APP and its products reverse endosomal phenotypes in the Ts65Dn mouse model

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