Potential involvement of intracellular pH in a mouse model of amyotrophic lateral sclerosis

Kuo, Su-Wei; Jiang, Mingchen; Heckman, C. J.

doi:10.3109/21678421.2013.850096

Cited by 12 publications

(15 citation statements)

References 10 publications

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“…More persistent G-quadruplex structure would cause increased genetic instability, DNA damage, and more efficient stalling of RNA-polymerase, which could aggravate downstream pathological consequences. Indeed, mice models of ALS show accelerated disease progression when intracellular environment is slightly acidified ( 61 ). Small changes in local pH influence whether AQU or NAN would be formed during transcription of C9orf72 .…”

Section: Discussionmentioning

confidence: 99%

NMR structure of a G-quadruplex formed by four d(G4C2) repeats: insights into structural polymorphism

Brčić

Plavec

2018

Nucleic Acids Research

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Most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is a largely increased number of d(G4C2)n•(G2C4)n repeats located in the non-coding region of C9orf72 gene. Non-canonical structures, including G-quadruplexes, formed within expanded repeats have been proposed to drive repeat expansion and pathogenesis of ALS and FTD. Oligonucleotide d[(G4C2)3G4], which represents the shortest oligonucleotide model of d(G4C2) repeats with the ability to form a unimolecular G-quadruplex, forms two major G-quadruplex structures in addition to several minor species which coexist in solution with K+ ions. Herein, we used solution-state NMR to determine the high-resolution structure of one of the major G-quadruplex species adopted by d[(G4C2)3G4]. Structural characterization of the G-quadruplex named AQU was facilitated by a single substitution of dG with 8Br-dG at position 21 and revealed an antiparallel fold composed of four G-quartets and three lateral C–C loops. The G-quadruplex exhibits high thermal stability and is favored kinetically and under slightly acidic conditions. An unusual structural element distinct from a C-quartet is observed in the structure. Two C•C base pairs are stacked on the nearby G-quartet and are involved in a dynamic equilibrium between symmetric N3-amino and carbonyl-amino geometries and protonated C+•C state.

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Section: Discussionmentioning

confidence: 99%

NMR structure of a G-quadruplex formed by four d(G4C2) repeats: insights into structural polymorphism

Brčić

Plavec

2018

Nucleic Acids Research

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“…In addition, acidification of neuronal cytosolic pH through glutamate and calcium overloading (excitotoxicity) are two crucial factors contributing to neurodegeneration (Kuo et al, ).…”

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confidence: 99%

Permissive role of cytosolic pH acidification in neurodegeneration: A closer look at its causes and consequences

Majdi

Mahmoudi

Sadigh-Eteghad

et al. 2016

J of Neuroscience Research

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The maintenance of cytosolic pH in its physiological range is required for normal neuronal activity, and even minor alterations can have serious consequences. This Review summarizes the current understanding of the conditions that are associated with cytosolic pH disruption and that lead to abnormal cytosolic acidification. Oxidative stress results in cytosolic acidification, and this plays a crucial role in the emergence of apoptosis in protein misfolding and excitotoxicity, ultimately leading to irreversible neuronal damage. Through the identification of mechanisms by which intraneuronal pH acidification promotes neurodegeneration, we may identify new approaches for preventing and treating neurodegenerative disorders. © 2016 Wiley Periodicals, Inc.

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“…Such an acidified intra and extracellular pH is also pathognomonic of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Huntington's Disease (HD), and is fundamental in the progression of these and other HNDDs [8,[10][11][12][13][14]. A low pHi and pHe rapidly decreases neuronal transmission and activity, preceding the onset of neural cell death by apoptosis [17][18][19][20][21], the same as ASIC1 does [22]. In the same vein, accumulation of β-amyloid (βA) is directly induced by acidosis [11][12][13][14][16][17][18][19][20][21][22]104,106,107] (Figure 2 and Box 1).…”

Section: Cellular and Microenvironmental Acid-base Abnormalities In Neurodegenerative Diseases (Box 1)mentioning

confidence: 99%

Hydrogen Ion Dynamics as the Fundamental Link Between Neurodegenerative Diseases and Cancer. Its Application to the Therapeutics of Neurodegenerative Diseases with Special Emphasis in Multiple Sclerosis

Harguindey¹,

Alfarouk²,

Orozco³

et al. 2022

Preprint

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The pH-related metabolic paradigm has rapidly grown in cancer research and treatment. In this contribution, this recent oncological perspective has been laterally for the first time in order to integrate neurodegeneration within the energetics of the cancer acid-base conceptual frame. At all levels of study, molecular, biochemical, metabolic and clinical, the intimate nature of both processes appears to be opposite mechanisms occurring at the far ends of a physiopathological intracellular pH/extracellular pH (pHi/pHe) spectrum. This wide-ranged original approach now permits an increase in our understanding of these opposite processes, cancer and neurodegeneration, and, as a consequence, allows to propose new avenues of treatment based upon the intracellular and microenvironmental hydrogen ion dynamics regulating and deregulating the biochemistry and metabolism of both cancer and neural cells. Under the same perspective, the etiopathogenesis and special characteristics of multiple sclerosis (MS) becomes an excellent model for the study of neurodegenerative diseases and, utilizing this pioneering approach, we find that MS appears to be a metabolic disease even before an autoimmune one. Also within this paradigm, several important aspects of MS, from mitochondrial failure to microbiota functional abnormalities, are analyzed in depth.

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Potential involvement of intracellular pH in a mouse model of amyotrophic lateral sclerosis

Cited by 12 publications

References 10 publications

NMR structure of a G-quadruplex formed by four d(G4C2) repeats: insights into structural polymorphism

NMR structure of a G-quadruplex formed by four d(G4C2) repeats: insights into structural polymorphism

Permissive role of cytosolic pH acidification in neurodegeneration: A closer look at its causes and consequences

Hydrogen Ion Dynamics as the Fundamental Link Between Neurodegenerative Diseases and Cancer. Its Application to the Therapeutics of Neurodegenerative Diseases with Special Emphasis in Multiple Sclerosis

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