Transcriptomic analysis reveals an association of FCGBP with Parkinson’s disease

Transcriptomics in Parkinson’s disease (PD) offers new insights into the molecular mechanism of PD pathogenesis. Several pathways, such as inflammation and protein degradation, have been identified by differential gene expression analysis. Our aim was to identify gene expression differences underlying the disease etiology and the discovery of pre-symptomatic risk biomarkers for PD from a multicenter study in the context of the PROPAG-AGEING project. We performed RNA sequencing from 47 patients with de novo PD, 10 centenarians, and 65 healthy controls. Using identified differentially expressed genes, functional annotations were assigned using gene ontology to unveil significant enriched biological processes. The expression of 16 selected genes was validated using OpenArray® assays and samples from independent cohorts of 201 patients with advanced PD, 340 healthy siblings of PD patients, and 177 healthy controls. Differential gene expression analysis identified higher FCGBP expression in patients with de novo PD compared with healthy controls and compared with centenarians. Furthermore, FCGBP showed no differences in terms of population origin or aging process. The increased FCGBP expression was validated in patients with advanced PD and their siblings. Thus, we provided evidence for an upregulation of FCGBP mRNA levels not only in patients with PD but also in individuals at putative higher risk of PD, suggesting that it could be important in gut–brain PD interaction, mediating the connection between microbiota and intestinal inflammatory processes, as well as neuroinflammation and neurodegeneration

Early downregulation of hsa-miR-144-3p in serum from drug-naïve Parkinson’s disease patients

open101siThis work was supported by the Horizon 2020 Framework Programme (Grant number 634821, PROPAG-AGING).Advanced age represents one of the major risk factors for Parkinson’s Disease. Recent biomedical studies posit a role for microRNAs, also known to be remodelled during ageing. However, the relationship between microRNA remodelling and ageing in Parkinson’s Disease, has not been fully elucidated. Therefore, the aim of the present study is to unravel the relevance of microRNAs as biomarkers of Parkinson’s Disease within the ageing framework. We employed Next Generation Sequencing to profile serum microRNAs from samples informative for Parkinson’s Disease (recently diagnosed, drug-naïve) and healthy ageing (centenarians) plus healthy controls, age-matched with Parkinson’s Disease patients. Potential microRNA candidates markers, emerging from the combination of differential expression and network analyses, were further validated in an independent cohort including both drug-naïve and advanced Parkinson’s Disease patients, and healthy siblings of Parkinson’s Disease patients at higher genetic risk for developing the disease. While we did not find evidences of microRNAs co-regulated in Parkinson’s Disease and ageing, we report that hsa-miR-144-3p is consistently down-regulated in early Parkinson’s Disease patients. Moreover, interestingly, functional analysis revealed that hsa-miR-144-3p is involved in the regulation of coagulation, a process known to be altered in Parkinson’s Disease. Our results consistently show the down-regulation of hsa-mir144-3p in early Parkinson’s Disease, robustly confirmed across a variety of analytical and experimental analyses. These promising results ask for further research to unveil the functional details of the involvement of hsa-mir144-3p in Parkinson’s Disease.openZago E.; Dal Molin A.; Dimitri G.M.; Xumerle L.; Pirazzini C.; Bacalini M.G.; Maturo M.G.; Azevedo T.; Spasov S.; Gomez-Garre P.; Perinan M.T.; Jesus S.; Baldelli L.; Sambati L.; Calandra Buonaura G.; Garagnani P.; Provini F.; Cortelli P.; Mir P.; Trenkwalder C.; Mollenhauer B.; Franceschi C.; Lio P.; Nardini C.; Adarmes-Gomez A.; Azevedo T.; Bacalini M.G.; Baldelli L.; Bartoletti-Stella A.; Bhatia K.P.; Marta B.-T.; Boninsegna C.; Broli M.; Dolores B.-R.; Calandra-Buonaura G.; Capellari S.; Carrion-Claro M.; Cilea R.; Clayton R.; Cortelli P.; Molin A.D.; De Luca S.; De Massis P.; Dimitri G.M.; Doykov I.; Escuela-Martin R.; Fabbri G.; Franceschi C.; Gabellini A.; Garagnani P.; Giuliani C.; Gomez-Garre P.; Guaraldi P.; Hagg S.; Hallqvist J.; Halsband C.; Heywood W.; Houlden H.; Huertas I.; Jesus S.; Jylhava J.; Labrador-Espinosa M.A.; Licari C.; Lio P.; Luchinat C.; Macias D.; Macri S.; Magrinelli F.; Rodriguez J.F.M.; Massimo D.; Maturo M.G.; Mengozzi G.; Meoni G.; Mignani F.; Milazzo M.; Mills K.; Mir P.; Mollenhauer B.; Nardini C.; Nassetti S.A.; Pedersen N.L.; Perinan-Tocino M.T.; Pirazzini C.; Provini F.; Ravaioli F.; Sala C.; Sambati L.; Scaglione C.L.M.; Schade S.; Schreglmann S.; Spasov S.; Strom S.; Tejera-Parrado C.; Tenori L.; Trenkwalder C.; Turano P.; Valzania F.; Ortega R.V.; Williams D.; Xumerle L.; Zago E.Zago E.; Dal Molin A.; Dimitri G.M.; Xumerle L.; Pirazzini C.; Bacalini M.G.; Maturo M.G.; Azevedo T.; Spasov S.; Gomez-Garre P.; Perinan M.T.; Jesus S.; Baldelli L.; Sambati L.; Calandra Buonaura G.; Garagnani P.; Provini F.; Cortelli P.; Mir P.; Trenkwalder C.; Mollenhauer B.; Franceschi C.; Lio P.; Nardini C.; Adarmes-Gomez A.; Azevedo T.; Bacalini M.G.; Baldelli L.; Bartoletti-Stella A.; Bhatia K.P.; Marta B.-T.; Boninsegna C.; Broli M.; Dolores B.-R.; Calandra-Buonaura G.; Capellari S.; Carrion-Claro M.; Cilea R.; Clayton R.; Cortelli P.; Molin A.D.; De Luca S.; De Massis P.; Dimitri G.M.; Doykov I.; Escuela-Martin R.; Fabbri G.; Franceschi C.; Gabellini A.; Garagnani P.; Giuliani C.; Gomez-Garre P.; Guaraldi P.; Hagg S.; Hallqvist J.; Halsband C.; Heywood W.; Houlden H.; Huertas I.; Jesus S.; Jylhava J.; Labrador-Espinosa M.A.; Licari C.; Lio P.; Luchinat C.; Macias D.; Macri S.; Magrinelli F.; Rodriguez J.F.M.; Massimo D.; Maturo M.G.; Mengozzi G.; Meoni G.; Mignani F.; Milazzo M.; Mills K.; Mir P.; Mollenhauer B.; Nardini C.; Nassetti S.A.; Pedersen N.L.; Perinan-Tocino M.T.; Pirazzini C.; Provini F.; Ravaioli F.; Sala C.; Sambati L.; Scaglione C.L.M.; Schade S.; Schreglmann S.; Spasov S.; Strom S.; Tejera-Parrado C.; Tenori L.; Trenkwalder C.; Turano P.; Valzania F.; Ortega R.V.; Williams D.; Xumerle L.; Zago E

Heterogeneity of prodromal Parkinson symptoms in siblings of Parkinson disease patients

A prodromal phase of Parkinson’s disease (PD) may precede motor manifestations by decades. PD patients’ siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had <1% probability of having prodromal PD; 100 between 1 and 10%, 26 siblings between 10 and 80%, one fulfilled the criteria for prodromal PD. According to the current analysis, we cannot confirm the increased risk of PD siblings for prodromal PD. Siblings showed a heterogeneous distribution of prodromal PD markers and probability. Additional parameters, including strong disease markers, should be investigated to verify if these results depend on validity and sensitivity of prodromal PD criteria, or if siblings’ risk is not elevated

A geroscience approach for Parkinson's disease: Conceptual framework and design of PROPAG-AGEING project

Advanced age is the major risk factor for idiopathic Parkinson's disease (PD), but to date the biological relationship between PD and ageing remains elusive. Here we describe the rationale and the design of the H2020 funded project “PROPAG-AGEING”, whose aim is to characterize the contribution of the ageing process to PD development. We summarize current evidences that support the existence of a continuum between ageing and PD and justify the use of a Geroscience approach to study PD. We focus in particular on the role of inflammaging, the chronic, low-grade inflammation characteristic of elderly physiology, which can propagate and transmit both locally and systemically. We then describe PROPAG-AGEING design, which is based on the multi-omic characterization of peripheral samples from clinically characterized drug-naïve and advanced PD, PD discordant twins, healthy controls and "super-controls", i.e. centenarians, who never showed clinical signs of motor disability, and their offspring. Omic results are then validated in a large number of samples, including in vitro models of dopaminergic neurons and healthy siblings of PD patients, who are at higher risk of developing PD, with the final aim of identifying the molecular perturbations that can deviate the trajectories of healthy ageing towards PD development

Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial functionassociated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD

Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability

Parkinson’s disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types

Defining the causes of sporadic Parkinson’s disease in the global Parkinson’s genetics program (GP2)

\ua9 2023, Springer Nature Limited. The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease

\ua9 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations