ABSTRACT
Insoluble protein inclusions accumulate in somatic cells in amyotrophic lateral sclerosis. The most common gene mutations associated with this pathology are SOD1 and C9orf72. Protein aggregates can be removed from cells by autophagy. We studied the relationship between the presence of genetic abnormalities in the SOD1 and C9orf72 genes and changes in autophagy in lymphomonocytes in amyotrophic lateral sclerosis. The study included 85 patients with amyotrophic lateral sclerosis and 15 healthy volunteers. Genetic analysis for the presence of mutations in the SOD1 and C9orf72 genes and detection of autophagy marker LC3 in lymphomonocytes were performed. In amyotrophic lateral sclerosis, autophagy activation in lymphomonocytes was found. We also obtained evidence that protein product of the mutant C9orf72 gene can disturb the late stages of autophagy.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Autophagy/genetics , C9orf72 Protein/genetics , Mutation , Superoxide Dismutase-1/genetics , Adult , Amyotrophic Lateral Sclerosis/immunology , Amyotrophic Lateral Sclerosis/pathology , C9orf72 Protein/immunology , Case-Control Studies , Female , Gene Expression , Humans , Lymphocytes/immunology , Lymphocytes/pathology , Male , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/immunology , Middle Aged , Monocytes/immunology , Monocytes/pathology , Superoxide Dismutase-1/immunologyABSTRACT
The article describes the first case of progressive multifocal leukoencephalopathy in a patient with multiple sclerosis, developed during treatment with natalizumab. The causes, possibly, influencing the outcome of the disease, are analyzed.
Subject(s)
Leukoencephalopathy, Progressive Multifocal , Multiple Sclerosis , Natalizumab/adverse effects , Humans , Leukoencephalopathy, Progressive Multifocal/chemically induced , Multiple Sclerosis/drug therapyABSTRACT
The molecular modeling method is promising for the assessment of protein structure, being able to present an energetically beneficial protein conformation with atomic precision. This method is of great importance for studying molecular interactions and confirming pathogenic significance of the changes in the protein structure caused by particular mutations. In the present study we used molecular modeling for the assessment of mutations in the SOD1 gene in patients with amyotrophic lateral sclerosis (ALS), a severe neurodegenerative disorder characterized by the loss of the spinal and cerebral motor neurons. The product of SOD1 is a cytosolic dimeric enzyme Cu/Zn superoxide dismutase (SOD1) responsible for detoxification of the cellular superoxide radicals. We showed that all 8 revealed coding point mutations of the gene led to moderate or significant changes of the SOD1 protein energy. Mutation His49Arg increased the protein energy, and reconstruction of the respective model pointed out to spatial destabilization of the molecule and abnormal interaction with the metal ion inside the active center. The other 7 mutations (Gly17Ala, Leu85Mal, Asn87Ser, Asp91Ala, Serl06Leu, Glu134Gly, and Leul45Phe), on the contrary, led to decrease of the protein energy and increase of the spatial stability of SOD1, which is usually accompanied by increased propensity of the 'inert' mutant molecule to misfolding and cellular aggregation. Thereby, the results of in silico analysis of the SOD1 gene mutations confirm staying of ALS within the class of the so-called conformational diseases of the central nervous system, a characteristic feature of which is forming of cytotoxic insoluble protein inclusions in neurons.
Subject(s)
Amyotrophic Lateral Sclerosis/metabolism , Models, Molecular , Protein Conformation , Superoxide Dismutase/chemistry , Amino Acid Sequence , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/pathology , Computer Simulation , Humans , Molecular Sequence Data , Mutation/genetics , Neurons/chemistry , Neurons/enzymology , Structure-Activity Relationship , Superoxide Dismutase/genetics , Superoxide Dismutase-1ABSTRACT
Genetic predisposition plays an important role in the development of amyotrophic lateral sclerosis (ALS). One of the most promising candidate genes in ALS is the vascular endothelial growth factor (VEGF) gene. In a Russian population, 192 ALS patients (103 males and 89 females), aged from 20 to 83 years (52.0±13.4), were examined. A control group comprised 128 age- and sex-matched people. All individuals studied were Slavs. Polymorphism -2578С/Ð (rs699947) in the VEGF gene was studied by real-time PCR. It was shown that the genotype distribution was significantly different between the ALS and control groups (χ2=11.1; Ñ=0.004); in the ALS cohort, the 2578A/A genotype was significantly more frequent (29.7% vs. 20.3%, p=0.04). The allele distribution was also significantly different between the two groups (χ2=4.4; Ñ=0.036). The -2578Ð/Ð genotype increased risk of ALS (OR 1.66; 95% CI 1.03-2.29), and this pattern was most obvious in the male subgroup (OR=2.18; 95% CI 1.90-2.47). It was found the association of the 'risk' 2578A/A genotype with the earlier disease onset and rapid progression. Therefore, the results obtained in the study confirm the role of the VEGF gene in the pathogenesis of ALS in a Russian population.
