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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which is characterized by the loss of both upper and lower motor neurons in the central nervous system. In a significant fraction of ALS cases - irrespective of family history- a genetic background may be identified. The genetic background of ALS shows a high variability from one ethnicity to another. The most frequent genetic cause of ALS is the repeat expansion of the C9orf72 gene. With the emergence of next-generation sequencing techniques and copy number alteration calling tools the focus in ALS genetics has shifted from disease causing genes and mutations towards genetic susceptibility and risk factors. In this review we aimed to summarize the most widely recognized and studied ALS linked repeat expansions and copy number variations other than the hexanucleotide repeat expansion in the C9orf72 gene. We compare and contrast their involvement and phenotype modifying roles in ALS among different populations. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a lethal multisystem neurodegenerative disease associated with progressive loss of motor neurons, leading to death. Not only is the clinical picture of ALS heterogenous, but also the pain sensation due to different types of pain involvement. ALS used to be considered a painless disease, but research has been emerging and depicting a more complex pain representation in ALS. Pain has been detected even a couple years before the symptomatic stage of ALS, referring to primary pain associated with muscle denervation, although secondary pain due to nociceptive causes is also a part of the clinical picture. A new non-contact dying-back injury mechanism theory of ALS recently postulated that the irreversible intrafusal proprioceptive Piezo2 microinjury could be the primary damage, with underlying genetic and environmental risk factors. Moreover, this Piezo2 primary damage is also proposed to dysregulate the primary pain pathways in the spinal dorsal horn in ALS due to the lost imbalanced subthreshold Ca2+ currents, NMDA activation and lost L-type Ca2+ currents, leading to the lost activation of wide dynamic range neurons. Our investigation is the first to show that the likely pathogenic variants of the Cav1.3 encoding CACNA1D gene may play a role in ALS pathology and the associated dysregulation or loss of the pain sensation. Furthermore, our reanalysis also shows that the SCN1A gene might also contribute to the dysregulated pain sensation in ALS. Finally, the absence of pathogenic variants of Piezo2 points toward the new non-contact dying-back injury mechanism theory of ALS. However, molecular and genetic investigations are needed to identify the functionally diverse features of this proposed novel critical pathway. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disease caused by complex interaction between genetic and environmental factors. There is a growing body of evidence of the involvement of sirtuins (SIRTs) in disease pathomechanism. SIRTs are NAD+-dependent histone deacetylases which take part in various cellular functions. However, available data of the relationship between SIRT gene polymorphisms and PD is limited. Our aim was to investigate the possible association of 10 SNPs identified within non-mitochondrial SIRTs, SIRT1, -2 and -6 with the risk of PD in Hungarian population, and to compare the expression level of these SIRTs between healthy controls and PD patients. Our results showed that rs3740051 and rs3818292 of SIRT1 and rs350843, rs350844, rs107251, rs350845 and rs350846 of SIRT6 show weak association with PD risk. On the contrary rs12778366 and rs3758391 of SIRT1 and rs10410544 of SIRT2 did not show association with PD. Moreover, we detected that mRNA level of SIRT1 was down-regulated, and mRNA level of SIRT6 was up-regulated, while SIRT2 mRNA level was not altered in the peripheral blood of PD patients as compared to controls. The difference in both cases was more pronounced when comparing the early-onset PD group to the control cohort. Nevertheless, mRNA level changes did not show any association with the presence of any of the investigated SNPs either in the PD or in the control group. In conclusion, our findings suggest that non-mitochondrial sirtuins, SIRT1 and -6 but not SIRT2 might contribute to the pathogenesis of PD in the Hungarian population both via their altered mRNA levels and via gene alterations identified as specific SNPs. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Considering the devastating symptoms, high prevalence, and lack of definitive diagnostic test, there is an urgent need to identify possible biomarkers and new therapeutic targets. Genes identified and/or proposed to be linked to PD encode proteins that fulfill diverse roles in cellular functions. There is a growing interest in identifying common traits which lead to the disease. Long non-coding RNAs have recently emerged as possible regulatory hubs of complex molecular changes affecting PD development. Among them, NEAT1 has attracted particular interest. It is a major component and the initiator of nuclear paraspeckles, thus regulating transcription and modifying protein functions. This review summarizes data available on the role of NEAT1 in PD. NEAT1 upregulation in PD has repeatedly been reported, however, whether this is part of a protective or a damaging mechanism is still a topic of debate. It has been proposed that NEAT1 propagates PD via its interaction with PINK1 and several micro RNAs and by modulating SNCA expression. On the other hand, findings of NEAT1 acting as a bona fide LRRK2 inhibitor argue for its protective role. These contradictory results could be due to the different disease models implemented. This calls attention to the difficulties posed by the complex patho-mechanisms of neurodegenerative disorders and the limitations of disease models. However, the potential of NEAT1 as a biomarker and as a therapeutic target for PD highly warrants further research to elucidate its exact role in this neurodegenerative disorder. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Behind the symptoms there is a complex pathological mechanism which leads to a dopaminergic cell loss in the substantia nigra pars compacta. Despite the strong efforts, curative treatment has not been found yet. To prevent a further cell death, numerous molecules were tested in terms of neuroprotection in preclinical (in vitro, in vivo) and in clinical studies as well. The aim of this review article is to summarize our knowledge about the extensively tested neuroprotective agents (Search period: 1991–2019). We detail the underlying pathological mechanism and summarize the most important results of the completed animal and clinical trials. Although many positive results have been reported in the literature, there is still no evidence that any of them should be used in clinical practice (Cochrane analysis was performed). Therefore, further studies are needed to better understand the pathomechanism of PD and to find the optimal neuroprotective agent(s). [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. Genetic factors play a key role in ALS, and identifying variants that contribute to ALS susceptibility is an important step toward understanding the etiology of the disease. The frequency of protein altering variants in ALS patients has been extensively investigated in populations of different ethnic origin. To further delineate the genetic architecture of the Hungarian ALS patients, we aimed to detect potentially damaging variants in major and minor ALS genes and in genes related to other neurogenetic disorders. A combination of repeat-sizing of C9orf72 and next-generation sequencing (NGS) was used to comprehensively assess genetic variations in 107 Hungarian patients with ALS. Variants in major ALS genes were detected in 36.45% of patients. As a result of repeat sizing, pathogenic repeat expansions in the C9orf72 gene were detected in 10 patients (9.3%). According to the NGS results, the most frequently mutated genes were NEK1 (5.6%), NEFH , SQSTM1 (3.7%), KIF5A , SPG11 (2.8%), ALS2 , CCNF , FUS , MATR3 , TBK1 , and UBQLN2 (1.9%). Furthermore, potentially pathogenic variants were found in GRN and SIGMAR1 genes in single patients. Additional 33 novel or rare known variants were detected in minor ALS genes, as well as 48 variants in genes previously linked to other neurogenetic disorders. The latter finding supports the hypothesis that common pathways in different neurodegenerative diseases may contribute to the development of ALS. While the disease-causing role of several variants identified in this study has previously been established, other variants may show reduced penetrance or may be rare benign variants. Our findings highlight the necessity for large-scale multicenter studies on ALS patients to gain a more accurate view of the genetic pattern of ALS. [ABSTRACT FROM AUTHOR]

The impairment of glutamatergic neurotransmission plays an important role in the development of Alzheimer's disease (AD). The pathological process, which involves the production of amyloid-β peptides and hyperphosphorylated tau proteins, spreads over well-delineated neuroanatomical circuits. The gradual deterioration of proper synaptic functioning (via GluN2A-containing N-methyl-D-aspartate receptors, NMDARs) and the development of excitotoxicity (via GluN2B-containing NMDARs) in these structures both accompany the disease pathogenesis. Although one of the most important therapeutic targets would be glutamate excitotoxicity, the application of conventional anti-glutamatergic agents could result in further deterioration of synaptic transmission and intolerable side-effects. With regard to NMDAR antagonists with tolerable side-effects, ion channel blockers with low affinity, glycine site agents, and specific antagonists of polyamine site and GluN2B subunit may come into play. However, in the mirror of experimental data, only the application of ion channel blockers with pronounced voltage dependency, low affinity, and rapid unblocking kinetics (e.g., memantine) and specific antagonists of the GluN2B subunit (e.g., ifenprodil and certain kynurenic acid amides) resulted in desirable symptom amelioration. Therefore we propose that these kinds of chemical agents may have therapeutic potential for present and future drug development. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder with a considerable socioeconomic burden. The pathomechanism of PD clearly involves the synergistic interaction of dopaminergic and glutamatergic dysfunctioning, including maladaptive corticostriatal synaptoplasticity. Most of the available treatment options have the aim of restoration of the physiological dopaminergic activity. Currently, the most widely used treatment is l-3,4-dihydroxyphenylalanine ( l-DOPA), which leads to the best symptomatic relief in PD. However, the long-term use of l-DOPA results in abnormal involuntary movements in almost all cases, the development of these dyskinetic movements also involving maladaptive corticostriatal synaptoplasticity. Perhaps chronic l-DOPA treatment has neurotoxic effects as well, but it has not yet been proved in clinical studies. Another important group of dopamine replacement therapy (DRT)-related side-effects consists of disinhibitory psychopathologies. Recent studies revealed that genetic polymorphisms affecting certain dopaminergic and glutamatergic receptors serve as independent risk factors for the development of these pathological conditions in PD patients. The available scientific data demonstrate that alterations in the kynurenine pathway of the tryptophan metabolism can be observed in PD and these alterations may contribute to the disease pathogenesis and to the occurrence of DRT-related side-effects. Therapeutic strategies that target the restoration of the kynurenine metabolism could therefore hold promise. [ABSTRACT FROM AUTHOR]

Abstract: A mitochondrial dysfunction causes an abatement in ATP production, the induction of oxidative damage and the propagation of cell death pathways. It is additionally closely related to both glutamate excitotoxicity and neuroinflammation. All of these interconnected aspects of a cellular dysfunction are involved in the pathogenesis of numerous neurological disorders, including those with an acute (e.g. ischemic stroke) or a chronic (e.g. Huntington''s disease) onset. Both acute and chronic neurodegenerative disorders have been demonstrated to involve multiple imbalances of the kynurenine pathway metabolism in the pathogenesis of the disease. As regards neuroactive compounds featuring in the pathway, quinolinic acid is a specific agonist of N-methyl-d-aspartate receptors, and a potent neurotoxin with additional and marked free radical-producing and lipid peroxidation-inducing properties. The toxic effects of 3-hydroxy-L-kynurenine are mediated by free radicals. Besides the possibility of increasing brain kynurenic acid concentrations, L-kynurenine may have vasoactive properties, too. Kynurenic acid has proven to be neuroprotective in several experimental settings, but in consequence of its pharmacokinetic properties it is not applicable as systemic administration in human cases. The aim of this short review is to emphasize the common features of cerebral ischemia and Huntington''s disease and to highlight therapeutic strategies targeting the kynurenine pathway. [Copyright &y& Elsevier]

Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder the pathomechanism of which is not yet fully known. With regard to the molecular mechanism of development of the disease, oxidative stress/mitochondrial impairment, glutamate excitotoxicity and neuroinflammation are certainly involved. Alterations in the kynurenine pathway, the main pathway of the tryptophan metabolism, can contribute to the complex pathomechanism. There are several possibilities for therapeutic intervention involving targeting of this altered metabolic route. The development of synthetic molecules that would shift the altered balance towards the achievement of neuroprotective effects would be of great promise for future clinical studies on PD. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a progressive neurodegenerative disorder, the pathomechanism of which is not yet fully understood. Excitotoxicity is known to be involved in the development of HD and antiglutamatergic agents may, therefore, have beneficial neuroprotective effects. One of these agents is the tryptophan metabolite kynurenic acid (KYNA), which is an endogenous NMDA receptor antagonist. However, its pharmacological properties rule out its systemic administration in CNS disorders. We have tested a novel KYNA analogue, N-(2- N, N-dimethylaminoethyl)-4-oxo-1 H-quinoline-2-carboxamide hydrochloride, in the N171-82Q transgenic mouse model of HD. The analogue exhibited several significant effects: it prolonged the survival of the transgenic mice, ameliorated their hypolocomotion, prevented the loss of weight and completely prevented the atrophy of the striatal neurons. The beneficial effects of this KYNA analogue are probably explained by its complex anti-excitotoxic activity. As it did not induce any appreciable side-effect at the protective dose applied in a chronic dosing regime in this mouse model, it appears worthy of further thorough investigations with a view to eventual clinical trials. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) and Huntington's disease (HD) are progressive chronic neurodegenerative disorders that are accompanied by a considerable impairment of the motor functions. PD may develop for familial or sporadic reasons, whereas HD is based on a definite genetic mutation. Nevertheless, the pathological processes involve oxidative stress and glutamate excitotoxicity in both cases. A number of metabolic routes are affected in these disorders. The decrease in antioxidant capacity and alterations in the kynurenine pathway, the main pathway of the tryptophan metabolism, are features that deserve particular interest, because the changes in levels of neuroactive kynurenine pathway compounds appear to be strongly related to the oxidative stress and glutamate excitotoxicity involved in the disease pathogenesis. Increase of the antioxidant capacity and pharmacological manipulation of the kynurenine pathway are therefore promising therapeutic targets in these devastating disorders. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with dementia as a main feature. Despite decades of thorough research in the field of AD, the pathomechanism is still not fully understood. The development of novel experimental models can help us in the discovery of both genetic and non-genetic components of disease pathogenesis. As currently available therapies in AD can provide merely moderate or only temporary symptomatic relief, there is a great demand for the development of new drugs with higher therapeutic potential. Some of the candidates would be those targeting the kynurenine pathway, the neuroactive metabolites of which are surely involved in both neurodegeneration and neuroprotection, mainly in relation with glutamate excitotoxicity and oxidative stress. Both analogs of the neuroprotective kynurenic acid and small molecule enzyme inhibitors preventing the formation of neurotoxic compounds may have potential therapeutic significance. However, there is a great need for new strategies to improve efficacy, transport across the blood-brain barrier and bioavailability, naturally with simultaneous minimization of the adverse side-effects. [ABSTRACT FROM AUTHOR]

Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by multifarious dysfunctional alterations including mitochondrial impairment. In the present study, the formation of inclusions caused by the mutation of huntingtin protein and its relationship with changes in energy metabolism and with pathological alterations were investigated both in transgenic and 3-nitropropionic acid-treated mouse models for HD. The HD and normal mice were characterized clinically; the affected brain regions were identified by immunohistochemistry and used for biochemical analysis of the ATP-producing systems in the cytosolic and the mitochondrial compartments. In both HD models, the activities of some glycolytic enzymes were somewhat higher. By contrast, the activity of glyceraldehyde-3-phosphate dehydrogenase was much lower in the affected region of the brain compared to that of the control. Paradoxically, at the system level, glucose conversion into lactate was enhanced in cytosolic extracts from the HD brain tissue, and the level of ATP was higher in the tissue itself. The paradox could be resolved by taking all the observed changes in glycolytic enzymes into account, ensuing an experiment-based detailed mathematical model of the glycolytic pathway. The mathematical modelling using the experimentally determined kinetic parameters of the individual enzymes and the well-established rate equations predicted the measured flux and concentrations in the case of the control. The same mathematical model with the experimentally determined altered Vmax values of the enzymes did account for an increase of glycolytic flux in the HD sample, although the extent of the increase was not predicted quantitatively. This suggested a somewhat altered regulation of this major metabolic pathway in HD tissue. We then used the mathematical model to develop a hypothesis for a new regulatory interaction that might account for the observed changes; in HD, glyceraldehyde-3-phosphate dehydrogenase may be in closer proximity (perhaps because of the binding of glyceraldehyde-3-phosphate dehydrogenase to huntingtin) with aldolase and engage in channelling for glyceraldehyde-3-phosphate. By contrast to most of the speculation in the literature, our results suggest that the neuronal damage in HD tissue may be associated with increased energy metabolism at the tissue level leading to modified levels of various intermediary metabolites with pathological consequences. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, with cases of either familial or sporadic origin. Several polymorphisms in a number of genes have been proved to have an important role in the development of PD. Particular attention has recently been paid to genes of the glucocerebrosidase (GBA) and the vacuolar protein sorting-associated protein 35 (VPS35). In this study, the three most common mutations (L444P, N370S and R120W) of the GBA gene and the D620N mutation of the VPS35 gene were examined in 124 Hungarian patients diagnosed with sporadic PD (SPD) and 122 control subjects. The frequency of the L444P mutation of the GBA gene proved to be higher in the PD patients (2.4%) than in the controls (0%), although the difference was not statistically significant. All the patients who carried the mutant allele were in the early-onset PD (EOPD) group. However, neither the R120W nor the N370S variant of the GBA gene nor D620N mutation of the VPS35 gene were detected among the PD cases or the controls. Even though these results suggest that the studied mutations are quite rare in SPD patients, the most frequent L444P mutation of the GBA gene may be associated with the development of EOPD in the Hungarian population. [ABSTRACT FROM AUTHOR]

Abstract: Huntington''s disease (HD) is one of the chronic devastating neurodegenerative disorders. The pathophysiological processes clearly involve both excitotoxicity and reduced gene transcription due to the decreased level of histone acetylation, accompanied by the loss of γ-aminobutyric acidergic (GABAergic) medium-sized spiny neurons in the striatum as a pathological hallmark of HD. Thus, the antiepileptic drug valproate, which has proved GABAergic, antiexcitotoxic and histone deacetylase inhibitor effects, might be of value by exerting a beneficial neuroprotective effect. We have now tested this drug in the N171-82Q transgenic mouse model of HD, following its chronic intraperitoneal administration in a daily dose of 100 mg/kg. Valproate significantly prolonged the survival of the transgenic mice and significantly ameliorated their diminished spontaneous locomotor activity, without exerting any noteworthy side-effect on their behaviour or the striatal dopamine content at the dose administered. The beneficial effect of valproate is probably explained by its complex pharmacological activity. As several previous clinical trials carried out with valproate did not indicate any positive effect in HD, it is worth considering the design of new studies based on a well-planned treatment regime with higher dose, using valproate in monotherapy or in combination therapy with a high number of participating patients. [Copyright &y& Elsevier]

• NEAT1 lncRNA regulates cellular and mitochondrial homeostasis. • Changes in NEAT1 level were reported in PD brain and in models of the disease. • We detected up-regulated NEAT1 level in leukocytes of PD patients. • NEAT1 up-regulation was most prominent among patients with long disease duration. Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder that poses serious burden to individuals and society as well. Although a number of PD associated genetic factors have been identified, the molecular mechanism of the disease so far has not been completely elucidated. Involvement of long non-coding RNAs (lncRNAs) in the pathology of neurodegenerative disorders is attracting increased interest because of the diverse mechanisms lncRNAs affect gene expression and cellular homeostasis at different levels. We aimed to test the feasibility of detecting alterations in lncRNA levels in easily accessible samples of PD patients by routine laboratory technique. By narrowing the number of selected lncRNAs implicated in neurodegeneration and increasing the number of PD samples included, we found one out of 41 lncRNAs readily detectable in increased level in peripheral blood of PD patients. We detected NEAT1 to be significantly up-regulated in PD patients in multiple comparisons. NEAT1 is the core element of nuclear paraspeckles and it plays role in regulation of transcription, mRNA and miRNA levels, mitochondrial and cellular homeostasis. Our finding is in accord with recent data demonstrating changes in the level of NEAT1 in neurons of PD patients and in several models of the disease. However, to our knowledge this is the first study to report NEAT1 up-regulation in blood of PD patients. Identification of altered expression of this lncRNA in the periphery might help to a better understanding of the mechanisms underlying PD, and can contribute to the identification of new therapeutic targets and disease markers. [ABSTRACT FROM AUTHOR]