Disbalance of zinc (Zn
2+
) and copper (Cu
2+
) ions in the central nervous system is involved in the pathogenesis of numerous neurodegenerative disorders such as multisystem atrophy, amyotrophic ...lateral sclerosis, Creutzfeldt-Jakob disease, Wilson-Konovalov disease, Alzheimer’s disease, and Parkinson’s disease. Among these, Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most frequent age-related neurodegenerative pathologies with disorders in Zn
2+
and Cu
2+
homeostasis playing a pivotal role in the mechanisms of pathogenesis. In this review we generalized and systematized current literature data concerning this problem. The interactions of Zn
2+
and Cu
2+
with amyloid precursor protein (APP), β-amyloid (Abeta), tau-protein, metallothioneins, and GSK3β are considered, as well as the role of these interactions in the generation of free radicals in AD and PD. Analysis of the literature suggests that the main factors of AD and PD pathogenesis (oxidative stress, structural disorders and aggregation of proteins, mitochondrial dysfunction, energy deficiency) that initiate a cascade of events resulting finally in the dysfunction of neuronal networks are mediated by the disbalance of Zn
2+
and Cu
2+
.
Thymoquinone is one of the main active components of the essential oil from black cumin (
Nigella sativa
) seeds. Thymoquinone exhibits a wide range of pharmacological activities, including ...neuroprotective action demonstrated in the models of brain ischemia/reperfusion, Alzheimer’s and Parkinson’s diseases, and traumatic brain injury. The neuroprotective effect of thymoquinone is mediated via inhibition of lipid peroxidation, downregulation of proinflammatory cytokines, maintenance of mitochondrial membrane potential, and prevention of apoptosis through inhibition of caspases-3, -8, and -9. Thymoquinone-based mitochondria-targeted antioxidants are accumulated in the mitochondria and exhibit neuroprotec-tive properties in nanomolar concentrations. Thymoquinone reduces the negative effects of acute and chronic forms of brain pathologies. The mechanisms of the pharmacological action of thymoquinone and its chemical derivatives require more comprehensive studying. In this paper, we formulated the prospects of application of thymoquinone and thymoquinone-based drugs in the therapy of neurodegenerative diseases.
Huntington’s disease (HD) is a severe autosomal dominant neurodegenerative disorder characterized by a combination of motor, cognitive, and psychiatric symptoms, atrophy of the basal ganglia and the ...cerebral cortex, and inevitably progressive course resulting in death 5–20 years after manifestation of its symptoms. HD is caused by expansion of CAG repeats in the
HTT
gene, which leads to pathological elongation of the polyglutamine tract within the respective protein-huntingtin. In this review, we present a modern view on molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. Main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as systemic failure of transcription, mitochondrial dysfunction and suppression of energy metabolism, abnormalities of cytoskeleton and axonal transport, microglial inflammation, decrease in synthesis of brain-derived neurotrophic factor, etc.
Disease modifying therapy for adult patients with SMA still raises certain questions regarding its effectiveness, given the long-term chronic process with often significant neurological deficits at ...the time of initiation of therapy. This paper presents three clinical cases of adult sitter patients with SMA type 2, who began risdiplam therapy 16.5-41 years after the disease onset. All patients have been receiving therapy since 2020, at the time of observation for 2.5-3 years. All patients showed subjective and objective (using specialized scales) improvement during long-term therapy with risdiplam. In addition to an increase in muscle strength, mainly in the proximal and distal parts of the arms, several non-motor effects were also noted (including improved swallowing and breathing), which cannot be recorded using scales. No adverse events were recorded during therapy.
Data on the participation of microbiota in the development of Parkinson’s disease allow us to discuss the ability of bacterial preparations to influence the processes leading to neurodegeneration. We ...studied the effect of oral administration of
Limosilactobacillus fermentum
U-21 lyophilisate on a model of Parkinson’s disease in rats induced by combined intranigral injection of LPS and systemic administration of paraquat. The toxins significantly increased the number of missteps in the “narrowing beam walking” test, but a tendency to a decrease in this parameter was shown after treatment with U-21. It should be noted that U-21 did not reduce the neuronal death in the substantia nigra, but mitigated the inflammatory glial response, decreased the accumulation of phosphorylated α-synuclein and complement protein C3. Our study demonstrated the efficiency of the combined model of parkinsonism and reduction of proinflammatory changes under the influence of pharmabiotic without changes in the nigral neuronal death and motor deficits.
•The largest Russian cohort of patients with mtDNA maintenance disorders was analysed.•Some peculiar features of the mutational spectra for the TWNK and the DGUOK genes were found.•High frequency of ...c.2243G > C mutation in the POLG gene was established.
Currently, pathogenic variants in more than 25 nuclear genes, involved in mtDNA maintenance, are associated with human disorders. mtDNA maintenance disorders manifest with a wide range of phenotypes, from severe infantile-onset forms of myocerebrohepatopathy to late-onset forms of myopathies, chronic progressive external ophthalmoplegia, and parkinsonism.
This study represents the results of molecular genetic analysis and phenotypes of 102 probands with mtDNA maintenance disorders. So far, this is the largest Russian cohort for this group of diseases. Mutations were identified in 10 mtDNA maintenance genes: POLG (n = 59), DGUOK (n = 14), TWNK (n = 14), TK2 (n = 8), MPV17 (n = 2), OPA3 (n = 1), FBXL4 (n = 1), RRM2B (n = 1), SUCLG1 (n = 1) and TYMP (n = 1). We review a mutation spectrum for the DGUOK and TWNK genes, that can be specific for the Russian population. In 34 patients we measured the blood mtDNA copy number and showed its significant reduction. Novel variants were found in 41 cases, which significantly expands the mutational landscape of mtDNA maintenance disorders.
IPSC line RCPCMi004-8 was generated from skin fibroblasts collected from a male patient with spinocerebellar ataxia 17. The patient has expanded trinucleotide CAG repeats in the TBP (TATA-binding ...protein) gene on chromosome 6q27. The reprogramming of fibroblasts was performed with Sendai viruses containing Oct-4, Sox-2, Klf-4, and c-Myc. Pluripotency was confirmed by immunofluorescence, RT-PCR, and the formation of embryoid bodies. The RCPCMi008-A cell line carries the same trinucleotide CAG repeats in the TBP gene. The RCPCMi008-A cell line can be used to model Spinocerebellar ataxia in vitro.
Parkinson’s disease (PD) is one of the most common movement disorders. It
is primarily diagnosed clinically. A correct diagnosis of PD in its early
stages is important for the development of a ...pathogenic treatment, which
necessitates a search for potential biomarkers of the disease. We evaluated the
diagnostic value of several microRNAs and their relationship with the clinical
characteristics of PD. The study included 70 PD patients and 40 healthy
volunteers. We analyzed the expression of 15 microRNAs in blood leukocytes,
which were selected based on literature data and modern concepts of molecular
PD pathogenesis. All patients were evaluated using the Hoehn and Yahr scale,
UPDRS, NMSQ, and PDQ-39. The data analysis revealed a statistically significant
increase in the expression of miR-7-5p, miR-29c-3p, and miR-185-5p and a
statistically significant decrease in the expression of miR-29a-3p and
miR-30c-1-5p in leukocytes in PD. However, the altered microRNA profile was
shown to have a moderate diagnostic value for PD diagnosis. MicroRNA expression
changes were associated with the motor and non-motor phenotypic features of PD
and administration of anti-Parkinson’s drugs. Also, a relationship
between some of the microRNAs studied and the duration and severity of PD was
found, which may potentially be used to monitor disease progression.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by death of motor neurons. To date, neither etiology nor pathogenesis of ALS are known, which leads to the absence of ...an effective treatment strategy. ALS patient-specific induced pluripotent stem cells (iPSCs) represent an excellent tool for the disease study. We obtained iPSCs line from peripheral blood mononuclear cells of the patient with homozygous Asp90Ala mutation in the SOD1 gene using non-integrating episomal vectors. The iPSCs line retained pathological genotype and expressed pluripotency markers. It also displayed a normal karyotype and the ability to differentiate into derivatives of three germ layers.
Problems in curing disorders of the brain are caused by several characteristic features of the nervous tissue, such as postmitotic nature of neurons, their limited reparative potential, significant ...energy dependence, etc. Because of special vulnerability and extremely high specialization, neurons are very sensitive to the action of any pathological factors, while existing possibilities of their trophic and metabolic support are scanty. Therefore, the creation of new reparative strategies, including substitutive cell technologies, is immediate task in neurology. Neurodegenerative disorders, Parkinson’s disease (PD), Huntington’s disease and others, are an “ideal” model for elaborating such strategies. As main motor symptoms of PD are related to degeneration of the dopaminergic nigrostriatal pathway, treatment of these patients, theoretically, may be based on transplantation of dopamine-producing neurons into the striatum. In the paper, analyzed are the results of many-year experimental (on models of parkinsonism) and preliminary clinical trials of neurotransplantation with the use of fetal tissues (dopaminergic cells of the ventral midbrain) and dopaminergic neurons differentiated from embryonal stem cells and induced pluripotent. Newest scientific achievements in this field, improvement of cell protocols and successful resolving of a number of technical and medical problems allow saying that neurotransplantation becomes clinical reality just before our eyes.
PDF
