Fiber deprivation and microbiome-borne curli shift gut bacterial populations and accelerate disease in a mouse model of Parkinson's disease.

peer reviewedParkinson's disease (PD) is a neurological disorder characterized by motor dysfunction, dopaminergic neuron loss, and alpha-synuclein (αSyn) inclusions. Many PD risk factors are known, but those affecting disease progression are not. Lifestyle and microbial dysbiosis are candidates in this context. Diet-driven gut dysbiosis and reduced barrier function may increase exposure of enteric neurons to toxins. Here, we study whether fiber deprivation and exposure to bacterial curli, a protein cross-seeding with αSyn, individually or together, exacerbate disease in the enteric and central nervous systems of a transgenic PD mouse model. We analyze the gut microbiome, motor behavior, and gastrointestinal and brain pathologies. We find that diet and bacterial curli alter the microbiome and exacerbate motor performance, as well as intestinal and brain pathologies, but to different extents. Our results shed important insights on how diet and microbiome-borne insults modulate PD progression via the gut-brain axis and have implications for lifestyle management of PD.Deciphering the impact of exposures from the gut microbiome-derived molecular complex in human health and diseas

The Imaging X-ray Polarimetry Explorer (IXPE): Technical Overview

The Imaging X-ray Polarimetry Explorer (IXPE) will expand the information space for study of cosmic sources, by adding linear polarization to the properties (time, energy, and position) observed in x-ray astronomy. Selected in 2017 January as a NASA Astrophysics Small Explorer (SMEX) mission, IXPE will be launched into an equatorial orbit in 2021. The IXPE mission will provide scientifically meaningful measurements of the x-ray polarization of a few dozen sources in the 2-8 keV band, including polarization maps of several x-ray-bright extended sources and phase-resolved polarimetry of many bright pulsating x-ray sources

An archaeal compound as a driver of Parkinson’s disease pathogenesis

Patients with Parkinson’s disease (PD) exhibit differences in their gut microbiomes compared to healthy individuals. Although differences have most commonly been described in the abundances of bacterial taxa, changes to viral and archaeal populations have also been observed. Mechanistic links between gut microbes and PD pathogenesis remain elusive but could involve molecules that promote α-synuclein aggregation. Here, we show that 2-hydroxypyridine (2-HP) represents a key molecule for the pathogenesis of PD. We observe significantly elevated 2-HP levels in faecal samples from patients with PD or its prodrome, idiopathic REM sleep behaviour disorder (iRBD), compared to healthy controls. 2-HP is correlated with the archaeal species Methanobrevibacter smithii and with genes involved in methane metabolism, and it is detectable in isolate cultures of M. smithii. We demonstrate that 2-HP is selectively toxic to transgenic α-synuclein overexpressing yeast and increases α-synuclein aggregation in a yeast model as well as in human induced pluripotent stem cell derived enteric neurons. It also exacerbates PD-related motor symptoms, α-synuclein aggregation, and striatal degeneration when injected intrastriatally in transgenic mice overexpressing human α-synuclein. Our results highlight the effect of an archaeal molecule in relation to the gut-brain axis, which is critical for the diagnosis, prognosis, and treatment of PD.

La Scienza e l'immaginario

L’attività di divulgazione della cultura scientifica ha un ruolo fondamentale sulla società, sia in termini di applicazioni innovative che di pianificazione dell’ambiente. I ricercatori dell’IAS-CNR di Capo Granitola operano da anni nell’ambito della diffusione della cultura scientifica, attraverso processi complessi e percorsi di divulgazione in partnership con istituti scolastici del territorio, realizzando attività seminariali, convegni direttamente nelle scuole, nonché visite didattiche guidate degli alunni nei laboratori dell’Istituto ed esperimenti interdisciplinari sull’ambiente marino. Tali processi divulgativi si sono sviluppati creando numerosi percorsi, in maniera per certi aspetti analoga a quella per cui dalla mescolanza dei tre colori fondamentali si è in grado di ottenere un numero pressoché illimitato di tinte diverse. Lo scopo di questa “mescolanza” è stato quello di ottenere un ventaglio di competenze e strumentazioni che consentissero di indagare i differenti aspetti dell’ecosistema marino da diversi punti di vista ed in maniera sinergica, tale da restituire un quadro il più ricco possibile di “tinte” e particolari. (Scienza e arte di Salvatore Mazzola) La Scienza e l'immaginario di Angela Cuttitta. Il progetto “La Scienza e l’Immaginario” nasce dalla collaborazione tra l’IAS - CNR di Capo Granitola e l’Accademia di Belle Arti di Palermo, che attraverso un approccio multidisciplinare ha voluto sperimentare l’unione tra il mondo scientifico e quello artistico, mettendo i giovani artisti, attraverso proiezioni e seminari scientifici, nelle condizioni di scoprire il mondo dell’ambiente marino e degli ecosistemi in esso presenti. Il progetto è nato dalla consapevolezza di come sia necessario operare sul piano della diffusione e divulgazione della cultura scientifica nei più vasti contesti sociali, a partire dall’ambito scolastico. Le azioni divulgative mirano, infatti, a diffondere la conoscenza dei processi geologici, chimico-fisici, climatici e biologici in modo pervasivo, non limitato a singole categorie/settori. La funzione strategica di tali azioni è quella di stimolare idee ed iniziative nonché di sviluppare una maggiore sensibilità nei confronti dei fenomeni che ci circondano, quale presupposto essenziale per una corretta programmazione politico-gestionale. Lo spirito che ha mosso tutte gli attori del progetto è stato quello di sensibilizzare gli studenti nei confronti della tutela delle risorse marine proprie del loro territorio e di sviluppare e promuovere la cultura come volano dello sviluppo sostenibile, della pace e dell’integrazione sociale, in armonia con quanto indicato dal Consiglio Europeo di Lisbona 2000. Grazie al lavoro di docenti e di ricercatori, l’arte come forma espressiva si è rivelata uno strumento valido e innovativo di divulgazione della cultura scientifica e ha portato alla creazione di suggestioni sui ragazzi che hanno percepito e realizzato forme e armonie espresse in questa mostra. L’impegno per questa manifestazione rappresenta, quindi, un appuntamento importante con le forze vive siciliane nel campo delle scienze del mare segnatamente ad esperti di biologia, chimica, fisica ed al mondo fantastico dell’arte, al fine di esprimere con le varie tecniche pittoriche un momento di riflessione culturale

Unravelling the early pathological mechanisms in Parkinson's Disease: Insights from alpha-synuclein dependent and independent models

Affecting over 10 million people worldwide, Parkinson’s disease is the second most common neurodegenerative disorder. With only 10% of cases having a known genetic cause, PD aetiology largely remains an enigma. Endogenous factors such as genetic predisposition, and exogenous factors such as exposure to toxins and lifestyle choices, interplay in the initiation and acceleration of the disease. Despite some common hallmarks such as nigrostriatal degeneration and Lewy bodies pathology, PD clinical picture largely varies across patients. Non-motor symptoms are common and thought to emerge up to 20 years prior to diagnosis, and they range from gastro-intestinal dysfunction to sleep disturbances to hallucinations. 90% of PD patients present at least one neuropsychiatric symptom, and about 30% of total patients develop dementia. Interventions aimed to prevent or slowdown disease progression require a better understanding of the early molecular events which foster neuronal dysfunction and death. Longitudinal studies which allow the investigation of early pathological stages are challenging to achieve on patients-based study only, thus largely rely on the use of animal models. Specifically, rodents have very similar anatomy, physiology, and genetics to humans, and a good set of genetic/molecular tools are available to generate pathological models. In the present thesis, we ventured into the investigation of alpha-synuclein dependent and independent models of PD, to unravel the early molecular events driving PD pathogenesis. Firstly, we investigated a genetic mouse model overexpressing the human, E46K mutated alpha-synuclein gene. We characterised neurodegeneration in the nigrostriatal pathway and motor deficits, detecting characteristics of an early-PD phenotype. Aiming to understand the molecular events driving neurodegeneration, we profiled the ventral midbrain transcriptome at different ages, uncovering that transcriptional changes are an early response to the alpha-synuclein challenge. Being the E46K mutation associated with dementia, we also profiled the hippocampus to investigate early transcriptional events linked with cognitive dysfunction in PD. We revealed that hippocampal dysfunction is mostly driven by the ageing process, operating over the interplay of genetic and gender predisposition. Secondly, we profiled transcriptomic changes in the midbrain of the alpha-synuclein independent, Park7-/- (DJ-1 KO) mouse model. Once again, we uncovered the interplay of sex and age in determining the susceptibility to the disease challenge, with males being more affected than females. Specifically, the response to DJ-1 loss of function appeared to be largely sex-specific, and to be mediated by the oestrogen pathway and the DJ-1/Nrf2/CYP1B1 axis. Even if sex-dimorphism has not been directly investigated in human Park7 PD cases due to their paucity, it has been reported in sporadic PD for several populations. Thus, our findings might significantly contribute to uncovering the reasons behind gender differences in PD. Thirdly, we investigated a moderate overexpressor of wild-type alpha-synuclein (Thy1-Syn14), aiming to reach a compromise between genetic and idiopathic PD modelling. To understand how endogenous and exogenous factors interplay in disease onset and progression, we exposed transgenic mice to the amyloidogenic protein Curli and to a fibre deprived diet. We uncovered that microbiome insults and diet act in combination to promote disease progression, and we provided supporting evidence to the concept of a gut-brain axis in PD. Our results underline the relevance of lifestyle adjustments in the management of PD patients. Finally, we investigated how different alpha-synuclein moieties and glutamate exposure might contribute to neurodegeneration. Even if these studies were left incomplete, we gained some preliminary indications which can represent a starting point for future research. We observed that both oligomers and fibrils are toxic forms of alpha-synuclein, and that a lack of standardisation in recombinant moieties production is a current issue that may halt reproducibility in alpha-synuclein research. We also reported a higher susceptibility of DJ-1 knock-down cells to glutamate excitotoxicity, potentially underlying an additional mechanism through which DJ-1 loss of function is responsible for PD development