Genetic analysis of amyotrophic lateral sclerosis identifies contributing pathways and cell types

Despite the considerable progress in unraveling the genetic causes of amyotrophic lateral sclerosis (ALS), we do not fully understand the molecular mechanisms underlying the disease. We analyzed genome-wide data involving 78,500 individuals using a polygenic risk score approach to identify the biological pathways and cell types involved in ALS. This data-driven approach identified multiple aspects of the biology underlying the disease that resolved into broader themes, namely, neuron projection morphogenesis, membrane trafficking, and signal transduction mediated by ribonucleotides. We also found that genomic risk in ALS maps consistently to GABAergic interneurons and oligodendrocytes, as confirmed in human single-nucleus RNA-seq data. Using two-sample Mendelian randomization, we nominated six differentially expressed genes (ATG16L2, ACSL5, MAP1LC3A, MAPKAPK3, PLXNB2, and SCFD1) within the significant pathways as relevant to ALS. We conclude that the disparate genetic etiologies of this fatal neurological disease converge on a smaller number of final common pathways and cell types

Marx, the labour theory of value and the transformation problem

This article reconsiders what Marx says about the transformation problem in Chapter IX of Capital Volume III, in the light of Marx's claim, made in Capital Volume I, that the value of a commodity is determined by the socially necessary labour time that goes into its production. The article criticises the traditional way of thinking about the transformation problem, according to which what Marx is doing in Chapter IX is considering the transformation of values into prices ('prices of production'). I argue that Marx's prices of production may be thought of as modified values. The discussion in Chapter IX is usually seen as a supplement to the labour theory of value. On this view its purpose is to explain how and why the prices of commodities sometimes deviate from their values. Against this view, the paper argues that Marx's remarks in Chapter IX can be seen as an elaboration on or development of the labour theory of value. It is a refinement of the account offered in Capital Volume I, which takes into consideration what Marx had in mind there when he introduced the notion of socially necessary as opposed to actual labour-time. The paper draws attention to the importance of Marx's distinction between the individual value of a commodity (determined by actual labour-time) and its social value (determined by socially necessary labour-time). It also draws attention to the methodological difficulties that are generated by any attempt to read Marx in this way

The impact of herpes zoster and post-herpetic neuralgia on quality-of-life

International audienceBACKGROUND: The potentially serious nature of herpes zoster (HZ) and the long-term complication post-herpetic neuralgia (PHN) are often underestimated. One in four people will contract herpes zoster in their lifetime, with this risk rising markedly after the age of 50 years, and affecting one in two in elderly individuals. Pain is the predominant symptom in all phases of HZ disease, being reported by up to 90% of patients. In the acute phase, pain is usually moderate or severe, with patients ranking HZ pain as more intense than post-surgical or labour pains. Up to 20% of patients with HZ develop PHN, which is moderate-to-severe chronic pain persisting for months or years after the acute phase. We review the available data on the effect of HZ and PHN on patients' quality-of-life. DISCUSSION: Findings show that HZ, and particularly PHN, have a major impact on patients' lives across all four health domains--physical, psychological, functional and social. There is a clear correlation between increasing severity of pain and greater interference with daily activities. Non-pain complications such as HZ ophthalmicus can increase the risk of permanent physical impairment. Some elderly individuals may experience a permanent loss of independence after an acute episode of HZ. Current challenges in the management of HZ and PHN are highlighted, including the difficulty in administering antiviral agents before pain becomes established and the limited efficacy of pain treatments in many patients. We discuss the clinical rationale for the HZ vaccine and evidence demonstrating that the vaccine reduces the burden of the disease. The Shingles Prevention Study, conducted among >38,000 people aged >or=60 years old, showed that the HZ vaccine significantly reduces the burden of illness and the incidence of both HZ and PHN. In the entire study population, zoster vaccination reduced the severity of interference of HZ and PHN with activities of daily living by two-thirds, as measured by two questionnaires specific to HZ. SUMMARY: A vaccination scheme may positively impact the incidence and course of HZ disease, thereby improving patients' quality-of-life

MiR-10 Represses HoxB1a and HoxB3a in Zebrafish

BACKGROUND: The Hox genes are involved in patterning the anterior-posterior axis. In addition to the protein coding Hox genes, the miR-10, miR-196 and miR-615 families of microRNA genes are conserved within the vertebrate Hox clusters. The members of the miR-10 family are located at positions associated with Hox-4 paralogues. No function is yet known for this microRNA family but the genomic positions of its members suggest a role in anterior-posterior patterning. METHODOLOGY/PRINCIPAL FINDINGS: Using sensor constructs, overexpression and morpholino knockdown, we show in Zebrafish that miR-10 targets HoxB1a and HoxB3a and synergizes with HoxB4 in the repression of these target genes. Overexpression of miR-10 also induces specific phenotypes related to the loss of function of these targets. HoxB1a and HoxB3a have a dominant hindbrain expression domain anterior to that of miR-10 but overlap in a weaker expression domain in the spinal cord. In this latter domain, miR-10 knockdown results in upregulation of the target genes. In the case of a HoxB3a splice variant that includes miR-10c within its primary transcript, we show that the microRNA acts in an autoregulatory fashion. CONCLUSIONS/SIGNIFICANCE: We find that miR-10 acts to repress HoxB1a and HoxB3a within the spinal cord and show that this repression works cooperatively with HoxB4. As with the previously described interactions between miR-196 and HoxA7 and Hox-8 paralogues, the target genes are located in close proximity to the microRNA. We present a model in which we postulate a link between the clustering of Hox genes and post-transcriptional gene regulation. We speculate that the high density of transcription units and enhancers within the Hox clusters places constraints on the precision of the transcriptional control that can be achieved within these clusters and requires the involvement of post-transcriptional gene silencing to define functional domains of genes appropriately

Both Stereoselective (R)- and (S)-1-Methyl-1,2,3,4-tetrahydroisoquinoline Enantiomers Protect Striatal Terminals Against Rotenone-Induced Suppression of Dopamine Release

1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is present in the human and rodent brain as a mixture of stereospecific (R)- and (S)-1MeTIQ enantiomers. The racemate, (R,S)-1MeTIQ, exhibits neuroprotective activity as shown in the earlier study by the authors, and In addition, it was suggested to play a crucial physiological role in the mammalian brain as an endogenous regulator of dopaminergic activity. In this article, we investigated the influence of stereospecific enantiomers of 1MeTIQ, (R)- and (S)-1MeTIQ (50 mg/kg i.p.) on rotenone-induced (3 mg/kg s.c.) behavioral and neurochemical changes in the rat. In behavioral study, in order to record dynamic motor function of rats, we measured locomotor activity using automated locomotor activity boxes. In biochemical studies, we analyzed in rat striatum the concentration of dopamine (DA) and its metabolites: intraneuronal DOPAC, extraneuronal 3-MT, and final HVA using HPLC with electrochemical detection. Otherwise, DA release was estimated by in vivo microdialysis study. The behavioral study has demonstrated that both acute and repeated (3 times) rotenone administration unimportantly depressed a basic locomotor activity in rat. (R)- and (S)-1MeTIQ stereoisomers (50 mg/kg i.p.) produced a modest behavioral activation both in naïve and rotenone-treated rats. The data from ex vivo neurochemical experiments have shown stereospecificity of 1MeTIQ enantiomers in respect of their effects on DA catabolism. (R)-1MeTIQ significantly increased both the level of the final DA metabolite, HVA (by about 70%), and the rate of DA metabolism (by 50%). In contrast to that, (S)-1MeTIQ significantly depressed DOPAC, HVA levels (by 60 and 40%, respectively), and attenuated the rate of DA metabolism (by about 60%). On the other hand, both the enantiomers increased the concentrations of DA and its extraneuronal metabolite, 3-MT in rat striatum. In vivo microdialysis study has shown that repeated but not acute administration of rotenone produced a deep and significant functional impairment of striatal DA release. Both (R)- and (S)- stereospecific enantiomers of 1MeTIQ antagonized rotenone-induced suppression of DA release; however, the effect of (R)-1MeTIQ was more strongly expressed in microdialysis study. In conclusion, we suggest that both chiral isomers of 1MeTIQ offer neuroprotection against rotenone-induced disturbances in the function of dopaminergic neurons and (R,S)-1MeTIQ will be useful as a drug with marked neuroprotective activity in the brain

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. // Methods: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. // Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. // Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations

Parkinson’s disease mouse models in translational research

Animal models with high predictive power are a prerequisite for translational research. The closer the similarity of a model to Parkinson’s disease (PD), the higher is the predictive value for clinical trials. An ideal PD model should present behavioral signs and pathology that resemble the human disease. The increasing understanding of PD stratification and etiology, however, complicates the choice of adequate animal models for preclinical studies. An ultimate mouse model, relevant to address all PD-related questions, is yet to be developed. However, many of the existing models are useful in answering specific questions. An appropriate model should be chosen after considering both the context of the research and the model properties. This review addresses the validity, strengths, and limitations of current PD mouse models for translational research

Interstitial lung disease in children - genetic background and associated phenotypes

Interstitial lung disease in children represents a group of rare chronic respiratory disorders. There is growing evidence that mutations in the surfactant protein C gene play a role in the pathogenesis of certain forms of pediatric interstitial lung disease. Recently, mutations in the ABCA3 transporter were found as an underlying cause of fatal respiratory failure in neonates without surfactant protein B deficiency. Especially in familiar cases or in children of consanguineous parents, genetic diagnosis provides an useful tool to identify the underlying etiology of interstitial lung disease. The aim of this review is to summarize and to describe in detail the clinical features of hereditary interstitial lung disease in children. The knowledge of gene variants and associated phenotypes is crucial to identify relevant patients in clinical practice

The multi-peak adaptive landscape of crocodylomorph body size evolution

Background: Little is known about the long-term patterns of body size evolution in Crocodylomorpha, the > 200-million-year-old group that includes living crocodylians and their extinct relatives. Extant crocodylians are mostly large-bodied (3–7 m) predators. However, extinct crocodylomorphs exhibit a wider range of phenotypes, and many of the earliest taxa were much smaller ( Results: Crocodylomorphs reached an early peak in body size disparity during the Late Jurassic, and underwent an essentially continual decline since then. A multi-peak Ornstein-Uhlenbeck model outperforms all other evolutionary models fitted to our data (including both uniform and non-uniform), indicating that the macroevolutionary dynamics of crocodylomorph body size are better described within the concept of an adaptive landscape, with most body size variation emerging after shifts to new macroevolutionary regimes (analogous to adaptive zones). We did not find support for a consistent evolutionary trend towards larger sizes among lineages (i.e., Cope’s rule), or strong correlations of body size with climate. Instead, the intermediate to large body sizes of some crocodylomorphs are better explained by group-specific adaptations. In particular, the evolution of a more aquatic lifestyle (especially marine) correlates with increases in average body size, though not without exceptions. Conclusions: Shifts between macroevolutionary regimes provide a better explanation of crocodylomorph body size evolution on large phylogenetic and temporal scales, suggesting a central role for lineage-specific adaptations rather than climatic forcing. Shifts leading to larger body sizes occurred in most aquatic and semi-aquatic groups. This, combined with extinctions of groups occupying smaller body size regimes (particularly during the Late Cretaceous and Cenozoic), gave rise to the upward-shifted body size distribution of extant crocodylomorphs compared to their smaller-bodied terrestrial ancestors.</p