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NRF2 as a Gene Modulator of Oxidative Stress in ALS Patients

This study explores the role of Nuclear factor erythroid 2-related factor 2 (NRF2) as a gene modulator in the oxidative stress response in patients with Amyotrophic Lateral Sclerosis (ALS). It investigates the association between functional polymorphisms in the NRF2 promoter gene and the risk of ALS, as well as their implications in molecular mechanisms underlying oxidative stress response.

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NRF2 as a Gene Modulator of Oxidative Stress in ALS Patients

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  1. Nuclear factor erythroid 2-related factor 2 come modulatore genico di risposta allo stress ossidativo in pazienti affetti da Sclerosi Laterale Amiotrofica. A. Lo Gerfo; L. Chico; L. Petrozzi; E. Caldarazzo-Ienco; C. Simoncini; V. Montano; C. Carlesi; E. Schirinzi; A. Galgani; F. Baldacci; F. Coppedè; A. Stoccoro; S. Daniele; G. Ricci; M. Mancusoe G. Siciliano

  2. ALS is a NDD characterized by progressive muscular paralysis, caused by the degeneration of motor neurons in the motor cortex primary, in the corticospinal tract and in the spinal cord. • Most ALS is sporadic; however, a small fraction of ALS is familial in origin. To date, around 20 genes are associated with ALS, with the most common causes of typical ALS associated with mutations in: • SOD1 • TARDBP • FUS • C9orf72

  3. ROS 8-OHdG 8-NitrodG Carbonylated proteins Nitrotyrosine Advanced protein oxidation products (AOPP) Nucleic acids Proteins Lipids ANTIOXIDANTS Sod Bilirubin GSH/GSSG Catalase Plasma thiols (-SH) GPx Iron-reducing capacity of plasma (FRAP)

  4. To evaluate a possible association between -653 A>G, - 651 G>A and -617 C>A functional polymorphisms in the NRF2 promoter gene, and the risk of ALS and their possible implication in molecular mechanisms that underlie the oxidative stress response.

  5. - 80° C -SH FRAP AOPP -like STUDY DESIGN 4. the possible association of the polymorphisms in the NRF2 gene promoter with the NRF2 transcript levels and oxidative stress biomarkers QIAamp DNA blood MINI kit (Qiagen) 3. the mRNA expression level by Real Time PCR in 13 ALS patients, 15 PD patients and 14 AD patients 1. the distribution of allelic and genotypic frequencies of the three functional single nucleotide polymorphisms (SNPs) -653 A> G, -651 G> A and -617 C> A in 154 ALS patients, 172 PD patients, 240 AD patients and 186 healthy controls; genotyping was carried out by DNA direct Sequencing DNA extraction 2. the plasma levels of some oxidative stress biomarkers in 73 ALS patients, 47 PD patients, 139 AD patients and 68 healthy controls ; in particular, we evaluated AOPP, FRAP and total plasma thiol groups. The biomarker levels were carried out by spectrophotometric methods Polymerase Chain Reaction (PCR) • Samples collection Sample amplification DNA sequencing 10’ 1000 x g 4°C • Evaluation of: Cycles

  6. Results

  7. CONCLUSION • Strong involvement of oxidative stress and a deficit of the Nrf2-ARE system in the pathogenesis of ALS; • It is possible to hypothesize that the -653G variant is able to attenuate the defence system directly controlled by Nrf2, making the G carriers more susceptible to oxidative insult; • -653G variant in NRF2 promoter gene is a common risk factor for ALS. • -653G variant is always associated to decreased level of NRF2 mRNA as evaluated in peripheral lymphocytes. • All together these underlines that Nrf2-ARE pathway can be one of the molecular mechanisms commonly involved in neurodegeneration. In agreement with other studies present in the literature, the results of this work indicate the Nrf2 pathway / ARE as an important mediator of neuroprotection and suggest this way as a possible therapeutic target for neurodegenerative diseases.

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