Annalisa Lo Gerfo

A Ser326Cys polymorphism in the DNA repair gene hOGG1 is not associated with sporadic Alzheimer's disease

Oxidative damage accumulates in the DNA of the human brain over time, and is supposed to play a critical role in the pathogenesis of Alzheimers disease (AD). It has been suggested that the brain in AD might be subjected to the double insult of increased oxidative stress, as well as deficiencies in repair mechanisms responsible for the removal of oxidized bases. The type of damage that is most likely to occur in neuronal cells is oxidative DNA damage which is primarily removed by the base excision repair (BER) pathway, and a decrease in BER activity was observed in post-mortem brain regions of AD individuals, especially in the activity of 8-oxoguanine DNA glycosylase. There is evidence that the Ser326Cys polymorphism of the human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene is associated with a reduced DNA repair activity. However, although a deficient BER was proposed in the etiology of AD by several authors, polymorphisms of BER genes have not been studied in AD yet. We performed a case-control study including 178 patients with sporadic AD (sAD) and 146 matched controls to evaluate the role of the Ser326Cys polymorphism as a risk factor for sAD. In the present study we failed to find any association between allele (chi2=0.03, p=0.86) or genotype (chi2=0.25, p=0.882) frequencies of hOGG1 Ser326Cys and the risk of sAD. Present results suggest that the Ser326Cys polymorphism of the hOGG1 gene is not an independent risk factor for sAD.

Association of the hOGG1 Ser326Cys polymorphism with sporadic amyotrophic lateral sclerosis

Amyotropic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disease causing the loss of motoneurons of the brain and the spinal cord. The etiology of ALS is still uncertain, but males are at increased risk for the disease than females. Several studies have suggested that motoneurons in ALS might be subjected to the double insult of increased DNA oxidative damage and deficiencies in DNA repair systems. Particularly, increased levels of 8-oxoguanine and impairments of the DNA base excision repair system have been observed in neurons of ALS patients. There is evidence that the Ser326Cys polymorphism of the human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene is associated with a reduced DNA repair activity. To evaluate the role of the hOGG1 Ser326Cys polymorphism in sporadic ALS (sALS), we screened 136 patients and 129 matched controls. In the total population, we observed association between both the Cys326 allele (p=0.02) and the combined Ser326Cys+Cys326Cys genotype (OR=1.65, 95% CI=1.06-2.88) and increased risk of disease. After stratification by gender, the Cys326 allele (p=0.01), both the Ser326Cys genotype (OR=2.14, 95% CI=1.09-4.19) and the combined Ser326Cys+Cys326Cys genotype (OR=2.15, 95% CI=1.16-4.01) were associated with sALS risk only in males. No significant association between the Ser326Cys polymorphism and disease phenotype, including age and site of onset and disease progression, was observed. Present results suggest a possible involvement of the hOGG1 Ser326Cys polymorphism in sALS pathogenesis.

DNMT3B Promoter Polymorphisms and Risk of Late Onset Alzheimer’s Disease

The vast majority of Alzheimers disease (AD) are late-onset forms (LOAD) likely due to the contribution of genetic, environmental, and stochastic factors, superimposed on a physiologically age-related decline of neuronal functions. Increasing evidence indicates epigenetic modifications in LOAD brains, and many of the environmental factors associated with AD risk, such as heavy metals and dietary factors, are able to modify the epigenome. There is also indication that environmentally-induced early life modifications of the genome during embryogenesis and brain development could contribute to the development of the disease later in life. DNA methyltransferase 3b (DNMT3b) is an enzyme involved in de novo methylation of the genome during embryogenesis, expressed in progenitor cells during neurogenesis. In the present study we evaluated two functional DNMT3B promoter polymorphisms, namely -149 C > T (rs2424913) and - 579 G > T (rs1569686), as candidate LOAD risk factors. Our analysis of 376 Italian LOAD patients and 308 matched controls revealed no difference in allele frequencies between the case an the control group (OR = 1.10 (0.88-1.39) for rs2424913, and OR = 1.02 (0.81-1.28) for rs1569686). Also the genotype distributions of both polymorphisms were closely similar between groups, and no significant effect on disease age at onset was observed. Overall, present results do not support a major role for rs2424913 or rs1569686 in LOAD pathogenesis.

Strategies for clinical approach to neurodegeneration in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disorder of unknown aetiology that involves the loss of upper and lower motor neurons in the cerebral cortex, brainstem and spinal cord. Significant progress in understanding the cellular mechanisms of motor neuron degeneration in ALS has not been matched with the development of therapeutic strategies to prevent disease progression, and riluzole remains the only available therapy, with only marginal effects on disease survival. More recently alterations of mRNA processing in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations have provided important insights into the molecular networks implicated in the disease pathogenesis. Here we review some of the recent progress in promoting therapeutic strategies for neurodegeneration.

Gly482Ser PGC-1α Gene Polymorphism and Exercise-Related Oxidative Stress in Amyotrophic Lateral Sclerosis Patients

The role of exercise in Amyotrophic lateral sclerosis (ALS) pathogenesis is controversial and unclear. Exercise induces a pleiotropic adaptive response in skeletal muscle, largely through the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional coactivator that regulates mitochondrial biogenesis and antioxidant defense mechanisms. It has been suggested that a Gly482Ser substitution in PGC-1α has functional relevance in human disorders and in athletic performance. To test this hypothesis, we examined the genotype distribution of PGC-1α Gly482Ser (1444 G > A) in ALS patients to evaluate whether or not the minor serine-encoding allele 482Ser is involved in oxidative stress responses during physical exercise. We genotyped 197 sporadic ALS patients and 197 healthy controls in order to detect differences in allelic frequencies and genotype distribution between the two groups. A total of 74 ALS patients and 65 controls were then comparatively assessed for plasmatic levels of the oxidative stress biomarkers, advanced oxidation protein products, ferric reducing ability and thiol groups. In addition a subgroup of 35 ALS patients were also assessed for total SOD and catalase plasmatic activity. Finally in 28 ALS patients we evaluated the plasmatic curve of the oxidative stress biomarkers and lactate during an incremental exercise test. No significant differences were observed in the genotype distribution and allelic frequency in ALS patients compared to the controls. We found significant increased advanced oxidation protein products (p < 0.001) and significant decreased ferric reducing ability (p < 0.001) and thiol groups (p < 0.001) in ALS patients compared to controls. When comparing different genotypes of PGC-1α, no relation between Gly482Ser polymorphism and oxidative stress biomarker levels was detected in resting conditions. On the other hand, when considering exercise performance, lactate levels were significantly higher (between p < 0.01 and p < 0.001) and greater protein oxidative products were found in AA (Ser482Ser) compared to GG (Gly482Gly) and GA (Gly482Ser) ALS patients. Our findings highlight the importance and confirm the involvement of oxidative stress in ALS pathogenesis. Although not associated with 1444 G > A SNP, ALS patients with Gly482Ser allelic variant show increased exercise-related oxidative stress. This thus highlights the possible role of this antioxidant defense transcriptional coactivator in ALS.

Effects of aerobic training on exercise-related oxidative stress in mitochondrial myopathies

In mitochondrial myopathies with respiratory chain deficiency impairment of energy cell production may lead to in excess reactive oxygen species generation with consequent oxidative stress and cell damage. Aerobic training has been showed to increase muscle performance in patients with mitochondrial myopathies. Aim of this study has been to evaluate, in 7 patients (6F e 1 M, mean age 44.9 ± 12.1 years) affected by mitochondrial disease, concomitantly to lactate exercise curve, the occurrence of oxidative stress, as indicated by circulating levels of lipoperoxides, in rest condition and as effect of exercise, and also, to verify if an aerobic training program is able to modify, in these patients, ox-redox balance efficiency. At rest and before training blood level of lipoperoxides was 382.4 ± 37.8 AU, compared to controls (318.7 ± 63.8; P < 0.05), this corresponding to a moderate oxidative stress degree according to the adopted scale. During incremental exercise blood level of lipoperoxides did not increase, but maintained significantly higher compared to controls. After an aerobic training of 10 weeks the blood level of lipoperoxides decreased by 13.7% at rest (P < 0.01) and 10.4%, 8.6% and 8.5% respectively at the corresponding times during the exercise test (P = 0.06). These data indicate that, in mitochondrial patients, oxidative stress occurs and that an aerobic training is useful in partially reverting this condition.

Association study between XRCC1 gene polymorphisms and sporadic amyotrophic lateral sclerosis

The aim of the present study was to investigate the possible contribution of three common functional polymorphisms in the DNA repair protein X-ray repair cross-complementing group 1 (XRCC1), namely Arg194Trp (rs1799782), Arg280His (rs25489) and Arg399Gln (rs25487), to sporadic amyotrophic lateral sclerosis (SALS). We genotyped 206 Italian SALS patients and 203 matched controls for XRCC1 Arg194Trp, Arg280His and Arg399Gln polymorphisms by means of PCR/RFLP technique, searching for association between any of the studied polymorphisms and disease risk, age and site of onset. We observed a statistically significant difference in XRCC1 Gln399 allele frequencies between SALS cases and controls (0.39/0.28; p=0.001). The present study suggests that the XRCC1 Arg399Gln polymorphism might contribute to SALS risk.

Twinkle mutation in an Italian family with external progressive ophthalmoplegia and parkinsonism: a case report and an update on the state of art.

The objective is to describe the clinical phenotype and genetic basis of a family with autosomal dominant progressive external ophthalmoplegia and parkinsonism with a Twinkle mutation. The proband, an 82 years old female, reported since childhood bilateral eyelid ptosis, ophthalmoplegia, sensorineural hypoacusis, mild depression since she was 45, with a positive familiar anamnesis of eyelid ptosis (father, two sisters and a son). She developed mild bilateral parkinsonism with a moderate clinical response to levodopa. The (123)I-FP-CIT SCAN evidenced a marked bilateral putaminal reduction and moderate caudate uptake reduction. Her 79 years old sister reported eyelid ptosis since she was 45 with ophthalmoplegia and developed a mild bilateral rest and postural tremor with moderate right arm plastic hypertonia when she was 76. The parkinsonism was confirmed with (123)I-FP-CIT SCAN. One of the two sons presented eyelid ptosis since he was 30 years old, with peripheral neuropathy with biopsy evidence of myopathy. We identified a G1750A mutation in the c10orf2 gene in the three patients. Mitochondrial dysfunction has been implicated in the pathogenesis of sporadic, idiopathic Parkinson disease (PD). In some cases, mitochondrial DNA primary genetic abnormalities or more commonly secondary rearrangements due to polymerase gamma (POLG) gene mutation can directly cause parkinsonism. Parkinsonism has been reported as a rare symptom associated to Twinkle (c10orf2). Parkinsonism has to be investigated in patients with PEO with analysis of Twinkle mutation.

Lack of association between the APEX1 Asp148Glu polymorphism and sporadic amyotrophic lateral sclerosis

Impairments in DNA repair enzymes have been observed in amyotrophic lateral sclerosis (ALS) tissues, particularly in the activity of the apurinic/apyrimidinic endonuclease 1 (APEX1). Moreover, it was suggested that the common APEX1 Asp148Glu polymorphism might be associated with ALS risk. To further address this question we performed the present study aimed at evaluating the contribution of the APEX1 Asp148Glu polymorphism in sporadic ALS (sALS) risk and clinical presentation, including age and site of onset and disease progression. We screened 134 sALS Italian patients and 129 matched controls for the presence of the APEX1 Asp148Glu polymorphism. No difference in APEX1 Asp148Glu allele and genotype frequencies was found between the groups, nor was the polymorphism associated with age and site of onset or disease progression. Present results do not support a role for the APEX1 Asp148Glu polymorphism in sALS pathogenesis in the Italian population.

Evidences of Reduced Antioxidant Activity in Patients With Chronic Migraine and Medication-Overuse Headache

Migraine is a complex multifactorial, neurobiological disorder, whose pathogenesis is not fully understood, nor are the mechanisms associated with migraine transformation from episodic to chronic pattern. A possible role of impaired oxidative mitochondrial metabolism in migraine pathogenesis has been hypothesized, and increased levels of peripheral markers of oxidative stress have been reported in migraine patients, although the literature data are limited and heterogeneous.