Homocysteine-induced acute excitotoxicity in cerebellar granule cells in vitro is accompanied by PP2A-mediated dephosphorylation of tau

Kuszczyk, Magdalena; Gordon‐Krajcer, Wanda; Łazarewicz, Jerzy W.

doi:10.1016/j.neuint.2009.02.010

Cited by 57 publications

(31 citation statements)

References 49 publications

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“…Although S199 phosphorylation is also found in tauopathies and promotes tau accumulation (Hanger et al, 2009), we report a relative loss of S199 phosphorylation in experimental glaucoma. Accumulating evidence indicates that some stress signals, including oxidative stress, excitotoxicity, and starvation, do not induce hyperphosphorylation but rather hypophosphorylation of tau (Davis et al, 1997;Kuszczyk et al, 2009;Mohamed et al, 2014). Furthermore, tau dephosphorylation has been reported following ischemia, hypoxia, and glucose deprivation in in vivo models and in human brain tissue (Shackelford and Nelson, 1996;Burkhart et al, 1998;Shackelford and Yeh, 1998;Mailliot et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Missorted tau in dendrites has been shown to target the postsynaptic protein Fyn and consequently to increase A␤-mediated excitotoxicity in mice (Ittner et al, 2010;Roberson et al, 2011). Microtubule breakdown accompanied by spine and mitochondrial loss occurs in dendrites invaded by missorted tau, a process mediated by the microtubule-severing enzyme spastin (Lacroix et al, 2010;Zempel et al, 2013). Of interest, emerging data indicate that ocular hypertension or acute optic nerve damage triggers rapid dendritic pathology in RGCs, which can lead to synaptic rearrangements, functional deficits, and death .…”

Section: Discussionmentioning

confidence: 99%

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Tau Accumulation, Altered Phosphorylation, and Missorting Promote Neurodegeneration in Glaucoma

et al. 2016

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Glaucoma, the leading cause of irreversible blindness worldwide, is characterized by the selective death of retinal ganglion cells (RGCs). Ocular hypertension is the most significant known risk factor for developing the disease, but the mechanism by which elevated pressure damages RGCs is currently unknown. The axonal-enriched microtubule-associated protein tau is a key mediator of neurotoxicity in Alzheimer's disease and other tauopathies. Using a well characterized in vivo rat glaucoma model, we show an age-related increase in endogenous retinal tau that was markedly exacerbated by ocular hypertension. Early alterations in tau phosphorylation, characterized by epitope-dependent hyperphosphorylation and hypophosphorylation, correlated with the appearance of tau oligomers in glaucomatous retinas. Our data demonstrate the mislocalization of tau in the somatodendritic compartment of RGCs subjected to high intraocular pressure. In contrast, tau was depleted from RGC axons in the optic nerve of glaucomatous eyes. Importantly, intraocular administration of short interfering RNA against tau effectively reduced retinal tau accumulation and promoted robust survival of RGC somas and axons, supporting a critical role for tau alterations in ocular hypertension-induced neuronal damage. Our study reveals that glaucoma displays signature pathological features of tauopathies, including tau accumulation, altered phosphorylation, and missorting; and identifies tau as a novel target to counter RGC neurodegeneration in glaucoma and prevalent optic neuropathies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tau Accumulation, Altered Phosphorylation, and Missorting Promote Neurodegeneration in Glaucoma

et al. 2016

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“…Homocysteine (Hcy) is a non-protein amino acid formed during metabolism of methionine. It significantly increases the tissue cell toxicity and subsequent oxidative damage (Ho et al 2002;Baydas et al 2008;Kuszczyk et al 2009). It seems that increased oxidative stress plays an important role in the pathogenesis and aetiology of chronic hyperhomocysteinaemia (Baydas et al 2003;Weiss 2005;Tyagi et al 2005;Taravati et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Effect of short-term administration of methionine on the ovary and uterus in a rat

et al. 2017

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Methionine is necessary for development but overuse of it can not only cause growth retardation but also damage organs such as the liver and cardiovascular system. The purpose of this research was to determine the effect of shortterm administration of methionine on the ovaries and uterus in a rat. Forty adult female rats were randomly allocated into four equal groups: each received 50, 100 or 200 mg/kg BW Lmethionine in 0.5 mL normal saline or just 0.5 mL normal saline (control) intraperitoneally for 20 days. On day 21, all rats were euthanized and tissues were taken for histological evaluation. Also, plasma homocysteine (Hcy) level was assessed in all groups. No difference was observed between the ovaries in all treatment and control groups; however, in methionine-injected groups, some histopathological changes were observed in the uterus such as atrophy in endometrial glands and the presence of inflammatory cells in the endo-and myometrium. Histopathological findings showed uterine infiltration of inflammatory cells in the methionine-injected groups which increased with increasing injected methionine levels. Also, all treatment groups showed increasing homocysteine levels compared to controls. These results show short-term administration of methionine and its associated homocysteinaemia has no effect on the ovary and its follicular structure.

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“…HHcy may play an excitotoxic effect through the activation of N-methyl-D-aspartate (NMDA)-glutamate receptors and contributes to an increased oxidative stress, formation of hydroxyl radicals, intracellular calcium influx, and apoptosis [24]. HHcy might also facilitate dephosphorylation of hippocampal tau-protein [25] and elevation of plasma Hcy is related to deficits of Hcy vitamin cofactors, such as vitamin B12, folate and vitamin B6. Several randomized controlled studies have reported that supplementation of B vitamins to lower Hcy could improve the cognitive function in individuals with or without existing cognitive impairment [26,27].…”

Section: Discussionmentioning

confidence: 99%

Hyperhomocysteinemia and Risk of Cognitive Decline: A Meta-Analysis of Prospective Cohort Studies

Nie

Xie

et al. 2014

Eur Neurol

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Objective: To evaluate the association between hyperhomocysteinemia (HHcy) and risk of cognitive decline. Methods: Electronic databases such as PubMed and EMBASE were searched for prospective cohort studies that involved the relationship between HHcy and risk of cognitive decline. Adjusted risk ratios (RRs) and corresponding 95% confidence intervals (95% CIs) were calculated by Review Manager 5.2.7. Subgroup analyses were conducted on stratification of some important variables. Results: Fourteen publications were included in the analysis. The pooled RR was 1.53 (95% CI, 1.23-1.91; p = 0.0002) for patients with HHcy compared to subjects without HHcy. Subgroup analyses indicated that the pooled RRs were 1.51 (95% CI, 1.10-2.05; p = 0.01) for more than five-year follow-up studies and 1. 56 (95% CI, 1.13-2.14; p = 0.007) for less than five-year follow-up studies. The pooled RRs were 1.66 (95% CI, 1.21-2.26; p = 0.001) for studies excluding the confounder of B vitamins and 1.34 (95% CI, 1.08-1.66; p = 0.008) for non-excluded studies. In terms of region, the pooled RR was 1.60 (95% CI, 1.21-2.13; p = 0.001) for European and American countries, while the pooled RR was 1.27 (95% CI, 1.02-1.59; p = 0.03) for other regions. Conclusion: As one of the independent risk factors, HHcy was associated with an increased risk of cognitive decline.

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Homocysteine-induced acute excitotoxicity in cerebellar granule cells in vitro is accompanied by PP2A-mediated dephosphorylation of tau

Cited by 57 publications

References 49 publications

Tau Accumulation, Altered Phosphorylation, and Missorting Promote Neurodegeneration in Glaucoma

Tau Accumulation, Altered Phosphorylation, and Missorting Promote Neurodegeneration in Glaucoma

Effect of short-term administration of methionine on the ovary and uterus in a rat

Hyperhomocysteinemia and Risk of Cognitive Decline: A Meta-Analysis of Prospective Cohort Studies

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