Xue Y et al. (2024) BMC Biol "The marine environmental microbiome mediates physiological outcomes in host nematodes"

Zhang L, Cao X, Xie Y, Xue Y

[BMC Biol, 2024]

Background: Nematodes are the most abundant metazoans in marine sediments, many of which are bacterivores; however, how habitat bacteria affect physiological outcomes in marine nematodes remains largely unknown. RESULTS: Here, we used a Litoditis marina inbred line to assess how native bacteria modulate host nematode physiology. We characterized seasonal dynamic bacterial compositions in L. marina habitats and examined the impacts of 448 habitat bacteria isolates on L. marina development, then focused on HQbiome with 73 native bacteria, of which we generated 72 whole genomes sequences. Unexpectedly, we found that the effects of marine native bacteria on the development of L. marina and its terrestrial relative Caenorhabditis elegans were significantly positively correlated. Next, we reconstructed bacterial metabolic networks and identified several bacterial metabolic pathways positively correlated with L. marina development (e.g., ubiquinol and heme b biosynthesis), while pyridoxal 5'-phosphate biosynthesis pathway was negatively associated. Through single metabolite supplementation, we verified CoQ10, heme b, acetyl-CoA, and acetaldehyde promoted L. marina development, while vitamin B6 attenuated growth. Notably, we found that only four development correlated metabolic pathways were shared between L. marina and C. elegans. Furthermore, we identified two bacterial metabolic pathways correlated with L. marina lifespan, while a distinct one in C. elegans. Strikingly, we found that glycerol supplementation significantly extended L. marina but not C. elegans longevity. Moreover, we comparatively demonstrated the distinct gut microbiota characteristics and their effects on L. marina and C. elegans physiology.Conclusions: Given that both bacteria and marine nematodes are dominant taxa in sedimentary ecosystems, the resource presented here will provide novel insights to identify mechanisms underpinning how habitat bacteria affect nematode biology in a more natural context. Our integrative approach will provide a microbe-nematodes framework for microbiome mediated effects on host animal fitness.

Teixeira-Castro A et al. (2015) Brain "Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease."

Esteves S, Duarte-Silva S, Oliveira S, Neto MF, Summavielle T, Jalles A, Silva-Fernandes A, Teixeira-Castro A, da Silva Santos L, Bessa J, Kang S, Miranda A, Oliveira P, Brielmann RM, Morimoto RI, Maciel P, Bessa C, Neves-Carvalho A, Silverman RB

[Brain, 2015]

Polyglutamine diseases are a class of dominantly inherited neurodegenerative disorders for which there is no effective treatment. Here we provide evidence that activation of serotonergic signalling is beneficial in animal models of Machado-Joseph disease. We identified citalopram, a selective serotonin reuptake inhibitor, in a small molecule screen of FDA-approved drugs that rescued neuronal dysfunction and reduced aggregation using a Caenorhabditis elegans model of mutant ataxin 3-induced neurotoxicity. MOD-5, the C. elegans orthologue of the serotonin transporter and cellular target of citalopram, and the serotonin receptors SER-1 and SER-4 were strong genetic modifiers of ataxin 3 neurotoxicity and necessary for therapeutic efficacy. Moreover, chronic treatment of CMVMJD135 mice with citalopram significantly reduced ataxin 3 neuronal inclusions and astrogliosis, rescued diminished body weight and strikingly ameliorated motor symptoms. These results suggest that small molecule modulation of serotonergic signalling represents a promising therapeutic target for Machado-Joseph disease.

Kawaguchi Y et al. (1994) Nat Genet "CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1."

Okamoto T, Katayama S, Kawakami H, Aizawa M, Kawaguchi Y, Taniwaki M, Akiguchi I, Nishimura M, Nakamura S, Inoue M

[Nat Genet, 1994]

We have identified a novel gene containing CAG repeats and mapped it to chromosome 14q32.1, the genetic locus for Machado-Joseph disease (MJD). In normal individuals the gene contains between 13 and 36 CAG repeats, whereas most of the clinically diagnosed patients and all of the affected members of a family with the clinical and pathological diagnosis of MJD show expansion of the repeat-number (from 68-79). Southern blot analyses and genomic cloning demonstrates the existence of related genes. These results raise the possibility that similar abnormalities in related genes may give rise to diseases similar to MJD.

Sudhaus W (1974) Zool. Jb. Syst. Bd. "Zur Systematik, Verbreitung, Okologie und Biologie neuer und wenig bekannter Rhabditiden (Nematoda) 2. Teil."

Sudhaus W

[Zool. Jb. Syst. Bd., 1974]

Five new species of the genus Rhabditis are described (Rh. riemanni n. sp., Rh. remanei n. sp., Rh. reciproca n. sp., Rh. blumi n. sp., and Rh. valida n. sp.) belonging to five subgenera (Crustorhabditis, Caenorhabditis, Rhabditis, Cephaloboides, and Pellioditis). The descriptions of four additional species are revised (Rh. ocypodis Chitwood, Rh. scanica Allgen, Rh. plicata Volk, and Rh. bengalensis Timm). The new subgenus Crustorhabditis n. subgen. derives from the paraphyletic subgenus Mesorhabditis. The species of the former group show a transition from living in littoral seaweed deposits to an obligate association with amphibious crabs (Crustacea). Information about the distribution, ecology, biology and ethology of all these species is presented (with two distribution maps, one for Rh. marina for comparison). Supplementary notes are given from Protorhabditis oxyuroides Sudhaus and Rhabditis tripartita von Linstow.

Pohl F et al. (2024) MicroPubl Biol "Pharmacological inhibition of acetylcholinesterase improves the locomotion defective phenotype of a SCA3 C. elegans model."

Kong Thoo Lin P, Lindsay-McGee V, Pohl F, Maciel P, Teixeira-Castro A

[MicroPubl Biol, 2024]

Inhibition of acetylcholinesterase (AChE) is a common used treatment option for Alzheimer's disease. However, there has been limited research on the potential use of AChE inhibitors for the treatment of Machado-Joseph disease (MJD)/Spinocerebellar Ataxia 3 (SCA3), in spite of the positive results using AChE inhibitors in patients with other inherited ataxias. MJD/SCA3, the most common form of dominant Spinocerebellar Ataxia worldwide, is caused by an expansion of the polyglutamine tract within the ataxin-3 protein, and is characterized by motor impairments. Our study shows that administration of the AChE inhibitor neostigmine is beneficial in treating the locomotion defective phenotype of a SCA3/MJD model of <i>C. elegans</i> and highlights the potential contribution of AChE enzymes to mutant ataxin-3-mediated toxicity.

Rodrigues AJ et al. (2007) FASEB J "Functional genomics and biochemical characterization of the C. elegans orthologue of the Machado-Joseph disease protein ataxin-3."

Geschwind DH, Costa MD, Ailion M, Maciel P, Santos C, Sequeiros J, Rodrigues AJ, Coppola G

[FASEB J, 2007]

Machado-Joseph disease (MJD) is the most common dominant spinocerebellar ataxia. MJD is caused by a CAG trinucleotide expansion in the ATXN3 gene, which encodes a protein named ataxin-3. Ataxin-3 has been proposed to act as a deubiquitinating enzyme in the ubiquitin-proteasome pathway and to be involved in transcriptional repression; nevertheless, its precise biological function(s) remains unknown. To gain further insight into the function of ataxin-3, we have identified the Caenorhabditis elegans orthologue of the ATXN3 gene and characterized its pattern of expression, developmental regulation, and subcellular localization. We demonstrate that, analogous to its human orthologue, C. elegans ataxin-3 has deubiquitinating activity in vitro against polyubiquitin chains with four or more ubiquitins, the minimum ubiquitin length for proteasomal targeting. To further evaluate C. elegans ataxin-3, we characterized the first known knockout animal models both phenotypically and biochemically, and found that the two C. elegans strains were viable and displayed no gross phenotype. To identify a molecular phenotype, we performed a large-scale microarray analysis of gene expression in both knockout strains. The data revealed a significant deregulation of core sets of genes involved in the ubiquitin-proteasome pathway, structure/motility, and signal transduction. This gene identification provides important clues that can help elucidate the specific biological role of ataxin-3 and unveil some of the physiological effects caused by its absence or diminished function.--Rodrigues, A-J., Coppola, G., Santos, C., do Carmo Costa, M., Ailion, M., Sequeiros, J., Geschwind, D. H., Maciel, P. Functional genomics and biochemical characterization of the C. elegans orthologue of the Machado-Joseph disease protein ataxin-3.

Gales L et al. (2005) J Mol Biol "Towards a structural understanding of the fibrillization pathway in Machado-Joseph's disease: trapping early oligomers of non-expanded ataxin-3."

Melo CV, Macedo-Ribeiro S, Maciel P, Clarke DT, Damas AM, Gales L, Cortes L, Costa MC, Almeida C

[J Mol Biol, 2005]

Machado-Joseph's disease is caused by a CAG trinucleotide repeat expansion that is translated into an abnormally long polyglutamine tract in the protein ataxin-3. Except for the polyglutamine region, proteins associated with polyglutamine diseases are unrelated, and for all of these diseases aggregates containing these proteins are the major components of the nuclear proteinaceous deposits found in the brain. Aggregates of the expanded proteins display amyloid-like morphological and biophysical properties. Human ataxin-3 containing a non-pathological number of glutamine residues (14Q), as well as its Caenorhabditis elegans (1Q) orthologue, showed a high tendency towards self-interaction and aggregation, under near-physiological conditions. In order to understand the discrete steps in the assembly process leading to ataxin-3 oligomerization, we have separated chromatographically high molecular mass oligomers as well as medium mass multimers of non-expanded ataxin-3. We show that: (a) oligomerization occurs independently of the poly(Q)-repeat and it is accompanied by an increase in beta-structure; and (b) the first intermediate in the oligomerization pathway is a Josephin domain-mediated dimer of ataxin-3. Furthermore, non-expanded ataxin-3 oligomers are recognized by a specific antibody that targets a conformational epitope present in soluble cytotoxic species found in the fibrillization pathway of expanded polyglutamine proteins and other amyloid-forming proteins. Imaging of the oligomeric forms of the non-pathological protein using electron microscopy reveals globular particles, as well as short chains of such particles that likely mimic the initial stages in the fibrillogenesis pathway occurring in the polyglutamine-expanded protein. Thus, they constitute potential targets for therapeutic approaches in Machado-Joseph's disease, as well as valuable diagnostic markers in disease settings.

Teixeira-Castro A et al. (2011) Hum Mol Genet "Neuron-specific proteotoxicity of mutant ataxin-3 in C. elegans: rescue by the DAF-16 and HSF-1 pathways."

Maciel P, Ailion M, Vilaca JL, Neves-Carvalho A, Jalles A, Morimoto RI, Dias N, Brignull HR, Rodrigues P, Oliveira JF, Teixeira-Castro A

[Hum Mol Genet, 2011]

The risk of developing neurodegenerative diseases increases with age. Although many of the molecular pathways regulating proteotoxic stress and longevity are well characterized, their contribution to disease susceptibility remains unclear. In this study, we describe a new Caenorhabditis elegans model of Machado-Joseph disease pathogenesis. Pan-neuronal expression of mutant ATXN3 leads to a polyQ-length dependent, neuron subtype-specific aggregation and neuronal dysfunction. Analysis of different neurons revealed a pattern of dorsal nerve cord and sensory neuron susceptibility to mutant ataxin-3 that was distinct from the aggregation and toxicity profiles of polyQ-alone proteins. This reveals that the sequences flanking the polyQ-stretch in ATXN3 have a dominant influence on cell-intrinsic neuronal factors that modulate polyQ-mediated pathogenesis. Aging influences the ATXN3 phenotypes which can be suppressed by the downregulation of the insulin/insulin growth factor-1-like signaling pathway and activation of heat shock factor-1.

Schmidt J et al. (2018) Adv Exp Med Biol "Animal Models of Machado-Joseph Disease."

Schmidt J, Schmidt T

[Adv Exp Med Biol, 2018]

Animal models are an important tool to study the pathophysiology of Machado-Joseph Disease (MJD). So far, animal models using simple organisms (like the round worm Caenorhabditis elegans or the fruit fly drosophila) but also mammalian models (mouse and even a non-human primate model) have been generated to study MJD. While simple organisms made an important contribution to the identification of pathophysiological mechanisms in MJD and were further used for modifier and screening purposes, mammalian models recapitulate major disease features of MJD in humans and are therefore a highly valuable tool for e.g. the validation of mechanisms or for pre-clinical validation of treatment approaches. Here we give an overview about the strategies which were used to model MJD and about the different models generated so far. We further highlight advantages of specific model organisms and describe the new findings which were made employing these animal models of MJD.

Vilasboas-Campos D et al. (2020) Free Radic Biol Med "Neurotherapeutic effect of Hyptis spp. leaf extracts in Caenorhabditis elegans models of tauopathy and polyglutamine disease: role of the glutathione redox cycle."

Dias ACP, Rios R, Maciel P, Vilasboas-Campos D, Silva FG, Bessa C, Teixeira-Castro A, Costa MD

[Free Radic Biol Med, 2020]

Hyptis suaveolens (HS), Hyptis pectinata (HP) and Hyptis marrubioides (HM) are plants used in folk medicine for treatment of several diseases. Here, we tested the in vivo antioxidant and neuroprotective potential of methanolic extracts from these plants, containing several rosmarinic acid derivatives and isoquercetin. In C. elegans, HS, HP and HM leaf extracts enhanced the antioxidant responses through the induction of specific antioxidant enzymes and demonstrated neurotherapeutic potential in transgenic models of genetically determined human neurodegenerative diseases - frontotemporal dementia with parkinsonism linked to chromosome 17 and Machado-Joseph disease. Chronic treatment of disease models with HS, HP and HM leaf extracts improved the animals' motor function and increased their tolerance to an oxidative insult. The restorative effect of HM extract in motor performance of both disease models required the presence of glutathione reductase (gsr-1), an enzyme that assures the glutathione redox cycle, highlighting the role of this pathway and unveiling a common candidate therapeutic target for these diseases. Our findings strengthen the relevance of plant-derived bioactive compound discovery for neurodegenerative disorders that remain without effective treatment.