Abstract:In the last twenty years, significant progress in understanding the pathophysiology of age-associated neurodegenerative diseases has been made. However, the prevention and treatment of these diseases remain without clinically significant therapeutic advancement. While we still hope for some potential genetic therapeutic approaches, the current reality is far from substantial progress. With this state of the issue, emphasis should be placed on early diagnosis and prompt intervention in patients with increased r… Show more
“…Our results are consistent with previous studies which show imbalanced GSH homeostasis in several models of ALS [72]. Interestingly, lack of GSH or, more generally, of cysteines redox balance, could play a role in the pathogenesis of neurodegenerative diseases [73].…”
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of the upper and lower motor neurons (MNs). About 10% of patients have a family history (familial, fALS); however, most patients seem to develop the sporadic form of the disease (sALS). SOD1 (Cu/Zn superoxide dismutase-1) is the first studied gene among the ones related to ALS. Mutant SOD1 can adopt multiple misfolded conformation, lose the correct coordination of metal binding, decrease structural stability, and form aggregates. For all these reasons, it is complicated to characterize the conformational alterations of the ALS-associated mutant SOD1, and how they relate to toxicity. In this work, we performed a multilayered study on fibroblasts derived from two ALS patients, namely SOD1L145F and SOD1S135N, carrying the p.L145F and the p.S135N missense variants, respectively. The patients showed diverse symptoms and disease progression in accordance with our bioinformatic analysis, which predicted the different effects of the two mutations in terms of protein structure. Interestingly, both mutations had an effect on the fibroblast energy metabolisms. However, while the SOD1L145F fibroblasts still relied more on oxidative phosphorylation, the SOD1S135N fibroblasts showed a metabolic shift toward glycolysis. Our study suggests that SOD1 mutations might lead to alterations in the energy metabolism.
“…Our results are consistent with previous studies which show imbalanced GSH homeostasis in several models of ALS [72]. Interestingly, lack of GSH or, more generally, of cysteines redox balance, could play a role in the pathogenesis of neurodegenerative diseases [73].…”
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of the upper and lower motor neurons (MNs). About 10% of patients have a family history (familial, fALS); however, most patients seem to develop the sporadic form of the disease (sALS). SOD1 (Cu/Zn superoxide dismutase-1) is the first studied gene among the ones related to ALS. Mutant SOD1 can adopt multiple misfolded conformation, lose the correct coordination of metal binding, decrease structural stability, and form aggregates. For all these reasons, it is complicated to characterize the conformational alterations of the ALS-associated mutant SOD1, and how they relate to toxicity. In this work, we performed a multilayered study on fibroblasts derived from two ALS patients, namely SOD1L145F and SOD1S135N, carrying the p.L145F and the p.S135N missense variants, respectively. The patients showed diverse symptoms and disease progression in accordance with our bioinformatic analysis, which predicted the different effects of the two mutations in terms of protein structure. Interestingly, both mutations had an effect on the fibroblast energy metabolisms. However, while the SOD1L145F fibroblasts still relied more on oxidative phosphorylation, the SOD1S135N fibroblasts showed a metabolic shift toward glycolysis. Our study suggests that SOD1 mutations might lead to alterations in the energy metabolism.
“…In the aging brain, an increased susceptibility of PDHC, NADP-isocitrate dehydrogenase (IDH-NADP), aconitase and glyceraldehyde-3-phosphate dehydrogenase to Zn and oxidative stress is linked with the presence of numerous cysteine–SH groups in their active centres, which require cytoprotective concentrations of glutathione, lipoamide and other free radical scavengers [ 14 , 106 , 107 ]. The synthesis of these species in aged brain decreases, whereas production of free radicals increases.…”
Section: Glucose and Pyruvate-derived Acetyl-coa Metabolism In Cholin...mentioning
confidence: 99%
“…As a result, several key enzymes of acetyl-CoA and energy metabolism are oxidatively modified [ 107 ]. This may be one of the causes of the increased incidence of Alzheimer’s disease and other neurodegenerative conditions in aged populations [ 106 , 108 ]. It would justify supplementation of those patients with N-acetyl-cysteine, tocopherol, glutathione or lipoamide as an adjuvant therapy [ 106 , 108 , 109 ].…”
Section: Glucose and Pyruvate-derived Acetyl-coa Metabolism In Cholin...mentioning
The human brain is characterised by the most diverse morphological, metabolic and functional structure among all body tissues. This is due to the existence of diverse neurons secreting various neurotransmitters and mutually modulating their own activity through thousands of pre- and postsynaptic interconnections in each neuron. Astroglial, microglial and oligodendroglial cells and neurons reciprocally regulate the metabolism of key energy substrates, thereby exerting several neuroprotective, neurotoxic and regulatory effects on neuronal viability and neurotransmitter functions. Maintenance of the pool of mitochondrial acetyl-CoA derived from glycolytic glucose metabolism is a key factor for neuronal survival. Thus, acetyl-CoA is regarded as a direct energy precursor through the TCA cycle and respiratory chain, thereby affecting brain cell viability. It is also used for hundreds of acetylation reactions, including N-acetyl aspartate synthesis in neuronal mitochondria, acetylcholine synthesis in cholinergic neurons, as well as divergent acetylations of several proteins, peptides, histones and low-molecular-weight species in all cellular compartments. Therefore, acetyl-CoA should be considered as the central point of metabolism maintaining equilibrium between anabolic and catabolic pathways in the brain. This review presents data supporting this thesis.
“…Gene therapy is a promising therapeutic strategy [ 2 ], which can be operated at the gene level to address the occurrence of diseases fundamentally [ 3 ] and provide more possibilities and flexibility than drug therapy [ 4 ]. Gene therapy will make great achievements in areas where there is no treatment or poor efficacy at present [ 5 ], especially in neurodegenerative diseases [ 6 , 7 ], congenital genetic diseases [ 8 , 9 ], and malignant tumors [ 10 , 11 ]. Among the reported methods for gene delivery, RNA interference (RNAi) has been studied and developed extensively [ 6 ].…”
Section: Introductionmentioning
confidence: 99%
“…Gene therapy will make great achievements in areas where there is no treatment or poor efficacy at present [ 5 ], especially in neurodegenerative diseases [ 6 , 7 ], congenital genetic diseases [ 8 , 9 ], and malignant tumors [ 10 , 11 ]. Among the reported methods for gene delivery, RNA interference (RNAi) has been studied and developed extensively [ 6 ]. RNAi refers to the phenomenon that small double-stranded RNA can specifically degrade or inhibit the expression of homologous mRNA, thus inhibiting or shutting down the expression of specific genes [ 12 , 13 , 14 , 15 ].…”
Gene therapy has attracted much attention because of its unique mechanism of action, non-toxicity, and good tolerance, which can kill cancer cells without damaging healthy tissues. siRNA-based gene therapy can downregulate, enhance, or correct gene expression by introducing some nucleic acid into patient tissues. Routine treatment of hemophilia requires frequent intravenous injections of missing clotting protein. The high cost of combined therapy causes most patients to lack the best treatment resources. siRNA therapy has the potential of lasting treatment and even curing diseases. Compared with traditional surgery and chemotherapy, siRNA has fewer side effects and less damage to normal cells. The available therapies for degenerative diseases can only alleviate the symptoms of patients, while siRNA therapy drugs can upregulate gene expression, modify epigenetic changes, and stop the disease. In addition, siRNA also plays an important role in cardiovascular diseases, gastrointestinal diseases, and hepatitis B. However, free siRNA is easily degraded by nuclease and has a short half-life in the blood. Research has found that siRNA can be delivered to specific cells through appropriate vector selection and design to improve the therapeutic effect. The application of viral vectors is limited because of their high immunogenicity and low capacity, while non-viral vectors are widely used because of their low immunogenicity, low production cost, and high safety. This paper reviews the common non-viral vectors in recent years and introduces their advantages and disadvantages, as well as the latest application examples.
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