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Dimebon belongs to a fast-growing group of "old" drugs that were suggested to be effective for therapy of pathological conditions different from their original targets. Following initial reports of successful Phase II clinical trials for mild-to-moderate Alzheimer's and Huntington's diseases, effects of Dimebon on various neurodegenerative conditions were investigated both in follow-up clinical trials and in various model systems. Although results of Phase III clinical trials carried out so far were disappointing, there is growing body of evidence that this drug can affect neuronal physiology in a way that would be beneficial at particular stages of development of certain types of neurodegeneration. To reveal what molecular and cellular pathological processes might be affected by Dimebon, we tested the ability of this drug to ameliorate pathology in model systems recapitulating particular pathogenic mechanisms involved in the development and progression of neurodegenerative diseases. Here we assessed the ability of Dimebon to modify several prominent features of tauopathies using transgenic tauP301S mice as a model. Chronic treatment with Dimebon was found to partially protect against the progressive decline in motor function and accumulation of tau-positive dystrophic neurons characteristic of tauP301S mice. Similar results were obtained with two further γ-carbolines structurally similar to Dimebon. Our data suggest that Dimebon and Dimebon-like compounds might be considered as drugs possessing disease-modifying activity for diseases with prominent tau pathology. [ABSTRACT FROM AUTHOR]

Recently, we characterized tumor suppressor candidate 5 (Tusc5) as an adipocyte-neuron PPARgamma target gene. Our objective herein was to identify additional genes that display distinctly high expression in fat and neurons, because such a pattern could signal previously uncharacterized functional pathways shared in these disparate tissues. gamma-Synuclein, a marker of peripheral and select central nervous system neurons, was strongly expressed in white adipose tissue (WAT) and peripheral nervous system ganglia using bioinformatics and quantitative PCR approaches. Gamma-synuclein expression was determined during adipogenesis and in subcutaneous (SC) and visceral adipose tissue (VAT) from obese and nonobese humans. Gamma-synuclein mRNA increased from trace levels in preadipocytes to high levels in mature 3T3-L1 adipocytes and decreased approximately 50% following treatment with the PPARgamma agonist GW1929 (P < 0.01). Because gamma-synuclein limits growth arrest and is implicated in cancer progression in nonadipocytes, we suspected that expression would be increased in situations where WAT plasticity/adipocyte turnover are engaged. Consistent with this postulate, human WAT gamma-synuclein mRNA levels consistently increased in obesity and were higher in SC than in VAT; i.e. they increased approximately 1.7-fold in obese Pima Indian adipocytes (P = 0.003) and approximately 2-fold in SC and VAT of other obese cohorts relative to nonobese subjects. Expression correlated with leptin transcript levels in human SC and VAT (r = 0.887; P < 0.0001; n = 44). Gamma-synuclein protein was observed in rodent and human WAT but not in negative control liver. These results are consistent with the hypothesis that gamma-synuclein plays an important role in adipocyte physiology. [ABSTRACT FROM AUTHOR]

The article reports on the assignment of phosphotriesterase-related gene (PIER) to human chromosome band 10p12 by in situ hybridization. Phosphotriesterases comprise a family of prokaryotic enzymes that catalyse the hydrolysis of various phosphotriester molecules. Eukaryotic phosphotriesterases have not yet been identified but recently mouse and rat cDNAs encoding proteins with a high degree of homology to these enzymes have been characterised. Human genomic clones encoding a phosphotriesterase homologue were isolated.

The malfunctioning of the brain synucleins is associated with pathogenesis of Parkinson's disease. Synucleins' ability to modulate various pre-synaptic processes suggests their modifying effects on the electroencephalogram (EEG) recorded from different brain structures. Disturbances in interrelations between them are critical for the onset and evolution of neurodegenerative diseases. Recently, we have shown that, in mice lacking several synucleins, differences between the frequency spectra of EEG from different brain structures are correlated with specificity of synucleins' combinations. Given that EEG spectra are indirect characteristics of inter-structural relations, in this study, we analyzed a coherence of instantaneous values for EEGs recorded from different structures as a direct measure of "functional connectivity" between them., Methods: EEG data from seven groups of knock-out (KO) mice with combined deletions of alpha, beta, and gamma synucleins versus a group of wild-type (WT) mice were compared. EEG coherence was estimated between the cortex (MC), putamen (Pt), ventral tegmental area (VTA), and substantia nigra (SN) in all combinations., Results: EEG coherence suppression, predominantly in the beta frequency band, was observed in KO mice versus WT littermates. The suppression was minimal in MC-Pt and VTA-SN interrelations in all KO groups and in all inter-structural relations in mice lacking either all synucleins or only beta synuclein. In other combinations of deleted synucleins, significant EEG coherence suppression in KO mice was dominant in relations with VTA and SN., Conclusion: Deletions of the synucleins produced significant attenuation of intra-cerebral EEG coherence depending on the imbalance of different types of synucleins.

α-, β-, and γ-Synuclein are intrinsically disordered proteins implicated in physiological processes in the nervous system of vertebrates. α-synuclein (αSyn) is the amyloidogenic protein associated with Parkinson's disease and certain other neurodegenerative disorders. Intensive research has focused on the mechanisms that cause αSyn to form amyloid structures, identifying its NAC region as being necessary and sufficient for amyloid assembly. Recent work has shown that a 7-residue sequence (P1) is necessary for αSyn amyloid formation. Although γ-synuclein (γSyn) is 55% identical in sequence to αSyn and its pathological deposits are also observed in association with neurodegenerative conditions, γSyn is resilient to amyloid formation in vitro. Here, we report a rare single nucleotide polymorphism (SNP) in the SNCG gene encoding γSyn, found in two patients with amyotrophic lateral sclerosis (ALS). The SNP results in the substitution of Met38 with Ile in the P1 region of the protein. These individuals also had a second, common and nonpathological, SNP in SNCG resulting in the substitution of Glu110 with Val. In vitro studies demonstrate that the Ile38 variant accelerates amyloid fibril assembly. Contrastingly, Val110 retards fibril assembly and mitigates the effect of Ile38. Substitution of residue 38 with Leu had little effect, while Val retards, and Ala increases the rate of amyloid formation. Ile38 γSyn also results in the formation of γSyn-containing inclusions in cells. The results show how a single point substitution can enhance amyloid formation of γSyn and highlight the P1 region in driving amyloid formation in another synuclein family member., Competing Interests: Competing interests statement:The authors declare no competing interest.

Synucleins, a family of three proteins highly expressed in neurons, are predominantly known for the direct involvement of α-synuclein in the etiology and pathogenesis of Parkinson's and certain other neurodegenerative diseases, but their precise physiological functions are still not fully understood. Previous studies have demonstrated the importance of α-synuclein as a modulator of various mechanisms implicated in chemical neurotransmission, but information concerning the involvement of other synuclein family members, β-synuclein and γ-synuclein, in molecular processes within presynaptic terminals is limited. Here, we demonstrated that the vesicular monoamine transporter 2-dependent dopamine uptake by synaptic vesicles isolated from the striatum of mice lacking β-synuclein is significantly reduced. Reciprocally, reintroduction, either in vivo or in vitro, of β-synuclein but not α-synuclein or γ-synuclein improves uptake by triple α/β/γ-synuclein-deficient striatal vesicles. We also showed that the resistance of dopaminergic neurons of the substantia nigra pars compacta to subchronic administration of the Parkinson's disease-inducing prodrug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine depends on the presence of β-synuclein but only when one or both other synucleins are absent. Furthermore, proteomic analysis of synuclein-deficient synaptic vesicles versus those containing only β-synuclein revealed differences in their protein compositions. We suggest that the observed potentiation of dopamine uptake by β-synuclein might be caused by different protein architecture of the synaptic vesicles. It is also feasible that such structural changes improve synaptic vesicle sequestration of 1-methyl-4-phenylpyridinium, a toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which would explain why dopaminergic neurons expressing β-synuclein and lacking α-synuclein and/or γ-synuclein are resistant to this neurotoxin., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: To assess effects of DF402, a bioisostere of Dimebon/Latrepirdine, on the disease progression in the transgenic model of amyotrophic lateral sclerosis (ALS) caused by expression of pathogenic truncated form of human FUS protein., Methods: Mice received DF402 from the age of 42 days and the onset of clinical signs, the disease duration and animal lifespan were monitored for experimental and control animals, and multiple parameters of their gait were assessed throughout the pre-symptomatic stage using CatWalk system followed by a bioinformatic analysis. RNA-seq was used to compare the spinal cord transcriptomes of wild-type, untreated, and DF402-treated FUS transgenic mice., Results: DF402 delays the onset and slows the progression of pathology. We developed a CatWalk analysis protocol that allows detection of gait changes in FUS transgenic mice and the effect of DF402 on their gait already at early pre-symptomatic stage. At this stage, a limited number of genes significantly change expression in transgenic mice and for 60% of these genes, DF402 treatment causes the reversion of the expression pattern., Conclusion: DF402 slows down the disease progression in the mouse model of ALS, which is consistent with previously reported neuroprotective properties of Dimebon and its other bioisosteres. These results suggest that these structures can be considered as lead compounds for further optimization to obtain novel medicines that might be used as components of complex ALS therapy., (© 2021 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Recent studies have implicated synucleins in several reactions during the biosynthesis of lipids and fatty acids in addition to their recognised role in membrane lipid binding and synaptic functions. These are among aspects of decreased synuclein functions that are still poorly acknowledged especially in regard to pathogenesis in Parkinson's disease. Here, we aimed to add to existing knowledge of synuclein deficiency (i.e., the lack of all three family members), with respect to changes in fatty acids and lipids in plasma, liver, and two brain regions in triple synuclein-knockout (TKO) mice. We describe changes of long-chain polyunsaturated fatty acids (LCPUFA) and palmitic acid in liver and plasma, reduced triacylglycerol (TAG) accumulation in liver and non-esterified fatty acids in plasma of synuclein free mice. In midbrain, we observed counterbalanced changes in the relative concentrations of phosphatidylcholine (PC) and cerebrosides (CER). We also recorded a notable reduction in ethanolamine plasmalogens in the midbrain of synuclein free mice, which is an important finding since the abnormal ether lipid metabolism usually associated with neurological disorders. In summary, our data demonstrates that synuclein deficiency results in alterations of the PUFA synthesis, storage lipid accumulation in the liver, and the reduction of plasmalogens and CER, those polar lipids which are principal compounds of lipid rafts in many tissues. An ablation of all three synuclein family members causes more profound changes in lipid metabolism than changes previously shown to be associated with γ-synuclein deficiency alone. Possible mechanisms by which synuclein deficiency may govern the reported modifications of lipid metabolism in TKO mice are proposed and discussed.