The thermolabile variant of 5,10-methylenetetrahydrofolate reductase is a possible risk factor for amyotrophic lateral sclerosis

Kühnlein, Peter; Jung, Hans H.; Farkas, Melinda; Keskitalo, Salla; Ineichen, Benjamin Victor; Jelčić, Ilijas; Petersen, Jens A.; Semmler, Alexander; Weller, Michael; Ludolph, Albert C.; Linnebank, Michael

doi:10.3109/17482968.2010.536985

Cited by 9 publications

(9 citation statements)

References 15 publications

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“…Similarly, the allele frequency analysis showed that the T allele confers risk for disease susceptibility (OR = 1.54; 95% CI = 1.05-2.29) (p = 0.03) (Table 2). The same results were found in studies by [72] and [73].…”

Section: Discussionsupporting

confidence: 89%

Do MTHFR C677T Genetic Polymorphism Influence in the Pathogenesis of Amyotrophic Lateral Sclerosis?

Azevedo

Santos

Oliveira

et al. 2021

Preprint

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Amyotrophic Lateral Sclerosis (ALS) is a progressive and lethal neurodegenerative disease without a definitive diagnostic test and effective treatment. A plethora of studies suggest that genetic factors play an important role in ALS development, and potentially link folate pathway dysregulation to disease pathogenesis. This study aims to evaluate folate dysregulation due to MTHFR C677T polymorphism and other factors such as sociodemographic and clinical, to better elucidate the involvement of these factors in ALS pathogenesis, and to investigate possible biomarkers for use as disease diagnostics or prognostics. This hospital-based case-control study analyzed 101 patients diagnosed with ALS and 119 considered healthy, with no suspicion or diagnosis of neurodegenerative disease. Blood samples were collected, stored, and underwent DNA extraction. Clinical and sociodemographic data from patients were collected through a questionnaire, as well as consultation of medical records. Genotypic analyses were performed using PCR-RFLP, and statistical analysis of clinical and genotypic data was conducted with SPSS software, version 23. The results show a higher presence of the mutant genotype (p = 0.02) in the case group, and suggest that mutant allele (T) is a risk factor for ALS susceptibility (OR = 1.54; 95% CI = 1.05–2.29; p = 0.03). Mutant genotype (T/T) interacts with both demographics (White p = 0.005 / Brown p = 0,001) and clinical factors (Physical activity p = 0.006) as risk factors for ALS. Also, a significant difference in alcohol consumption (p = 0.001) between the case and control group was observed. Moreover, a statistical trend towards faster disease progression and death was observed for patients with the mutant allele (T) (p = 0.06). Thus, the results of this study suggest that folate deficiency due to MTHFR C677T polymorphism is implicated in ALS through pathogenic mechanisms and interaction with other risk factors, resulting in faster disease progression and early death.

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Section: Discussionsupporting

confidence: 89%

Do MTHFR C677T Genetic Polymorphism Influence in the Pathogenesis of Amyotrophic Lateral Sclerosis?

Azevedo

Santos

Oliveira

et al. 2021

Preprint

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“…However, conflicting data should also be mentioned. Thus, while some authors found a link between MTHFR C677T polymorphisms as risk factors for ALS (Kühnlein et al, 2011 ; Sazci et al, 2012 ) others (Ricci et al, 2012 ) did not detect a direct association between the two.…”

Section: Discussionmentioning

confidence: 95%

“…Inherited deficiency of the enzyme methylenetetrahydrofolate reductase (MTHFR), transforming HCY into methionine through remethylation, is associated with severe muscular hypotonia (Huemer et al, 2015 ). There is conflicting evidence about the role of the frequent MTHFR C677T polymorphisms as risk factors for ALS (Kühnlein et al, 2011 ; Ricci et al, 2012 ; Sazci et al, 2012 ). The variant MTHFR C677T, known to be associated with increased levels of HCY (Kang et al, 1988 ; Li et al, 2003 ) is more frequent among ALS patients (Kühnlein et al, 2011 ), however an Italian population study found no association (Ricci et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

“…There is conflicting evidence about the role of the frequent MTHFR C677T polymorphisms as risk factors for ALS (Kühnlein et al, 2011 ; Ricci et al, 2012 ; Sazci et al, 2012 ). The variant MTHFR C677T, known to be associated with increased levels of HCY (Kang et al, 1988 ; Li et al, 2003 ) is more frequent among ALS patients (Kühnlein et al, 2011 ), however an Italian population study found no association (Ricci et al, 2012 ). Apart from a direct link between MTHFR and ALS, there are other possible mechanisms how the increasing level of HCY due to aging or improper diet (Zhang et al, 2008 ; Song et al, 2013 ) can speed up the development of disease in patients with ALS.…”

Section: Introductionmentioning

confidence: 99%

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Homocysteine aggravates ROS-induced depression of transmitter release from motor nerve terminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia

Bukharaeva

Shakirzyanova

Khuzakhmetova

et al. 2015

Front. Cell. Neurosci.

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Homocysteine (HCY) is a pro-inflammatory sulphur-containing redox active endogenous amino acid, which concentration increases in neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). A widely held view suggests that HCY could contribute to neurodegeneration via promotion of oxidative stress. However, the action of HCY on motor nerve terminals has not been investigated so far. We previously reported that oxidative stress inhibited synaptic transmission at the neuromuscular junction, targeting primarily the motor nerve terminals. In the current study, we investigated the effect of HCY on oxidative stress-induced impairment of transmitter release at the mouse diaphragm muscle. The mild oxidant H2O2 decreased the intensity of spontaneous quantum release from nerve terminals (measured as the frequency of miniature endplate potentials, MEPPs) without changes in the amplitude of MEPPs, indicating a presynaptic effect. Pre-treatment with HCY for 2 h only slightly affected both amplitude and frequency of MEPPs but increased the inhibitory potency of H2O2 almost two fold. As HCY can activate certain subtypes of glutamate N-methyl D-aspartate (NMDA) receptors we tested the role of NMDA receptors in the sensitizing action of HCY. Remarkably, the selective blocker of NMDA receptors, AP-5 completely removed the sensitizing effect of HCY on the H2O2-induced presynaptic depressant effect. Thus, at the mammalian neuromuscular junction HCY largely increases the inhibitory effect of oxidative stress on transmitter release, via NMDA receptors activation. This combined effect of HCY and local oxidative stress can specifically contribute to the damage of presynaptic terminals in neurodegenerative motoneuron diseases, including ALS.

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“…SNPs in the gene encoding the ESR1 co‐activator PPARGC1A are associated with age of ALS onset and survival in males specifically . Moreover, genetic variations in MTHFR – which encodes an important enzyme in the folate cycle – and in the promoter region of the growth factor VEGFA have been associated with ALS in women. These notions imply that the presumed hormonal neuroprotective advantage of women could be counteracted by genetic variations in, for example, the folate cycle and/or VEGF signaling.…”

Section: Discussionmentioning

confidence: 99%

Integrated molecular landscape of amyotrophic lateral sclerosis provides insights into disease etiology

et al. 2017

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Amyotrophic lateral sclerosis (ALS) is a severe, progressive and ultimately fatal motor neuron disease caused by a combination of genetic and environmental factors, but its underlying mechanisms are largely unknown. To gain insight into the etiology of ALS, we here conducted genetic network and literature analyses of the top-ranked findings from six genome-wide association studies of sporadic ALS (involving 3589 cases and 8577 controls) as well as genes implicated in ALS etiology through other evidence, including familial ALS candidate gene association studies. We integrated these findings into a molecular landscape of ALS that allowed the identification of three main processes that interact with each other and are crucial to maintain axonal functionality, especially of the long axons of motor neurons, i.e. (1) Rho-GTPase signaling; (2) signaling involving the three regulatory molecules estradiol, folate, and methionine; and (3) ribonucleoprotein granule functioning and axonal transport. Interestingly, estradiol signaling is functionally involved in all three cascades and as such an important mediator of the molecular ALS landscape. Furthermore, epidemiological findings together with an analysis of possible gender effects in our own cohort of sporadic ALS patients indicated that estradiol may be a protective factor, especially for bulbar-onset ALS. Taken together, our molecular landscape of ALS suggests that abnormalities within three interconnected molecular processes involved in the functioning and maintenance of motor neuron axons are important in the etiology of ALS. Moreover, estradiol appears to be an important modulator of the ALS landscape, providing important clues for the development of novel disease-modifying treatments.

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The thermolabile variant of 5,10-methylenetetrahydrofolate reductase is a possible risk factor for amyotrophic lateral sclerosis

Cited by 9 publications

References 15 publications

Do MTHFR C677T Genetic Polymorphism Influence in the Pathogenesis of Amyotrophic Lateral Sclerosis?

Do MTHFR C677T Genetic Polymorphism Influence in the Pathogenesis of Amyotrophic Lateral Sclerosis?

Homocysteine aggravates ROS-induced depression of transmitter release from motor nerve terminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia

Integrated molecular landscape of amyotrophic lateral sclerosis provides insights into disease etiology

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