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Common and rare variants in theLRRK2locus are associated with Parkinson’s disease (PD) risk, but the downstream effects of these variants on protein levels remains unknown. We performed comprehensive proteogenomic analyses using the largest aptamer-based CSF proteomics study to date (7,006 aptamers (6,138 unique proteins) in 3,107 individuals). We identified eleven independent SNPs in theLRRK2locus associated with the levels of 26 proteins as well as PD risk. Of these, only eleven proteins have been previously associated with PD risk (e.g., GRN or GPNMB). Proteome-wide association study (PWAS) analyses suggested that the levels of ten of those proteins were genetically correlated with PD risk and seven were validated in the PPMI cohort. Mendelian randomization analyses identified five proteins (GPNMB, GRN, HLA-DQA2, LCT, and CD68) causal for PD and nominate one more (ITGB2). These 26 proteins were enriched for microglia-specific proteins and trafficking pathways (both lysosome and intracellular). This study not only demonstrates that protein phenome-wide association studies (PheWAS) and trans-protein quantitative trail loci (pQTL) analyses are powerful for identifying novel protein interactions in an unbiased manner, but also thatLRRK2is linked with the regulation of PD-associated proteins that are enriched in microglial cells and specific lysosomal pathways.

Extracellular vesicles are secreted by a wide variety of cells, and their primary functions include intercellular communication, immune responses, human reproduction, and synaptic plasticity. Their molecular cargo reflects the physiological processes that their cells of origin are undergoing. Thus, many studies have suggested that extracellular vesicles could be a promising biomarker tool for many diseases, mainly due to their biological relevance and easy accessibility to a broad range of body fluids. Moreover, since their biological composition leads them to cross the blood-brain barrier bidirectionally, growing evidence points to extracellular vesicles as emerging mirrors of brain diseases processes. In this regard, this review explores the biogenesis and biological functions of extracellular vesicles, their role in different physiological and pathological processes, their potential in clinical practice, and the recent outstanding studies about the role of exosomes in major human brain diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), or brain tumors., A. Cano acknowledges the support of the Instituto de Salud Carlos III (ISCIII) under the grant Sara Borrell (CD22/00125) and Ministerio de Ciencia e Innovación, Proyectos de Generación de Conocimiento grant PID2021-122473OA-I00. Authors acknowledge the services of ProofreadingServices.com for English correction. Authors acknowledge the support of the Ministerio de Ciencia e Innovación, Proyectos de Generación de Conocimiento grants PID2019-106625RB-I00 and PID2021-123462OB-I00. ISCIII Acción Estratégica en Salud, integrated in the Spanish National R+D+I Plan and financed by ISCIII Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER “Una manera de hacer Europa") grant PI17/01474, PI19/00335, PI22/01403 and PI22/00258. The support of CIBERNED (ISCIII) under the grants CB06/05/2004 and CB18/05/00010. The support from PREADAPT project. Joint Program for Neurodegenerative Diseases (JPND) grant Nº AC19/00097, from HARPONE Project, Agency for Innovation and Entrepreneurship (VLAIO) grant Nº PR067/21, and from DESCARTES project, German Research Foundation (DFG). The support of Fundación bancaria “La Caixa” and Grífols SA (GR@ACE project).

BackgroundGenome-wide Association Studies (GWAS) have reshaped our understanding of the genetic bases of complex diseases in general and neurodegenerative diseases in particular. Despite being a common disorder, dementia with Lewy bodies (DLB), which, together with Parkinson’s disease dementia (PDD), comprise the umbrella term Lewy body dementias (LBD), is far from being well-characterized genetically. This is primarily due to a lack of familial cases and difficulty recruiting large, deeply characterized cohorts, given the high rate of misdiagnosis. By performing the largest GWAS in DLB, we aimed to identify novel risk loci to gain a better understanding of this disease’s pathobiology.MethodsHere, we conducted the largest meta-analysis of genome-wide association studies performed in LBD, using a total of 5,119 cases and 20,988 controls, from five independent datasets, aggregating all previously published DLB genome-wide association results to date, as well as two previously undescribed cohorts. Additionally, we performed a sex stratified GWAS using the discovery datasets. We updated the heritability estimates for DLB and, to fine map these estimates, we used local heritability analysis. We calculated genetic correlation estimates between DLB and a range of other diseases and traits to identify potential pleiotropy. We also performed gene-set analysis to identify genes with excess burden of rare variability and pathway analysis. Lastly, we used the UK Biobank data to perform a PheWas using individuals at the extremes of genetic risk for DLB.FindingsBetween November 2018 and September 2022 we analyzed 8.6 million single nucleotide polymorphisms in 3293 DLB cases, 1826 LBD cases and 20,988 controls, as well as phenotypes from the UK Biobank dataset. Despite more than doubling the sample size from the previous GWAS in DLB, we did not identify significant loci in addition to those previously reported atGBA, SNCA, STX1B, andAPOE. However, the sex-stratified analysis revealed that theGBAandSNCAsignals are mainly driven by males, suggesting a sex-specific genetic architecture of disease. Using only clinical and neuropathologically diagnosed cases, we highlight four loci surpassing the significance threshold. Using the largest cohort of DLB we update our heritability estimates to 13% and fine map these results highlighting regions of the genome with high heritability but no genome-wide significant result so far.InterpretationThese data provide the most comprehensive analysis of genetic variability in DLB to date. The fact that no novel risk loci have been identified after doubling the cohort size indicates the potentially significant role of rare variants in the genetic architecture of DLB and stresses the urgent need for larger, well-characterized cohorts of this disease for genetic studies. The sex-stratified analysis shows that males and females have different signatures of genetic risk for DLB. These results have widespread implications for clinical practice and clinical trials’ design in DLB.

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event occurring exclusively in men and has been previously associated with Alzheimer’s disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomization to construct an age-independent polygenic risk score of mLOY (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per SD unit (p=4.22·10−20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in males with mild cognitive impairment (HR=1.23; p=0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group. The male-specificity of the observed effects suggests that these associations of mLOY with AD are caused by the inherent loss of the Y chromosome, and not by the increased genomic instability underlying mLOY risk. Additionally, we found that blood mLOY phenotype was associated with increased CSF levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis. Furthermore, we encourage researchers to use this mloy-PRS instrument to find unbiased associations between mLOY and ageing-related diseases.

Using genome-wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s (PD) or Alzheimer’s (AD) disease versus controls across ancestry groups. A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2x10-13; AD: OR=0.91[0.89; 0.93]; p=1.8x10-22), and with a protective HLA association recently reported in amyotrophic lateral sclerosis (ALS). Hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03, and absent for HLA-DRB1*04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brains and was more strongly associated with tau levels than Aβ42 levels in the cerebrospinal fluid. Finally, protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. An HLA-DRB1*04-mediated adaptive immune response, potentially against tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8,074; replication n = 5,042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for amyloid beta 42 (Aβ42) and BIN1 for phosphorylated Tau (pTau). GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories (amyloid, astrocyte, processing & migration, and migration & motility) suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

This frontiers article highlights recent developments on the application of transition metal-based zwitterionic complexes in catalysis. Recent applications of selected zwitterionic catalysts in polymerization reactions, including the carbonylative polymerization of cyclic ethers, carbon–carbon coupling reactions, the asymmetric hydrogenation of unfunctionalized olefins, and the hydrofunctionalization of alkenes are reviewed. In addition, advances in the field of hydrogenation/dehydrogenation reactions related to energy applications, including the hydrogenation of CO2 and the dehydrogenation of formic acid and N-heterocycles, the functionalization of CO2 with amines and hydrosilanes, and the valorization of polyfunctional bio-based feedstocks, such as the dehygrogenation of glycerol to lactic acid or the reduction of levulinic acid into γ-valerolactone, are also described., Financial support from the Spanish Ministerio de Ciencia e Innovación (MICINN/FEDER) under the Project PID2019-103965GB-I00/AEI/10.13039/501100011033, and the “Departamento de Ciencia, Universidad y Sociedad del Conocimiento del Gobierno de Aragón” (group E42_20R) is gratefully acknowledged.

Using genome-wide association data, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s (PD) or Alzheimer’s (AD) disease versus controls across ancestry groups. A shared genetic association was observed across diseases at rs601945 (PD: odds ratio (OR)=0.84; 95% confidence interval, [0.80; 0.88]; p=2.2×10−13; AD: OR=0.91[0.89; 0.93]; p=1.8×10−22), and with a protective HLA association recently reported in amyotrophic lateral sclerosis (ALS). Hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03, and absent for HLA-DRB1*04:05. The same signal was associated with decreased neurofibrillary tangles (but not neuritic plaque density) in postmortem brains and was more strongly associated with Tau levels than Aβ42 levels in the cerebrospinal fluid. Finally, protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone Tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. An HLA-DRB1*04-mediated adaptive immune response, potentially against Tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.

The zwitterionic complex [Cp*IrCl{(MeIm)CHCOO}] (1) efficiently catalyzes the selective hydrosilylation of CO to afford the corresponding silylformate. The best reaction performance has been achieved in acetonitrile at 348 K using HSiMePh. The 1-catalyzed reaction of pyrrolidine with CO and HSiMePh strongly depends on the CO pressure. At low concentration of CO (1 bar) formation of the corresponding silylcarbamate, by insertion of CO into the Si−N bond of the in situ generated silylamine was observed, while at higher pressure (3 bar) the formamide derivative was obtained as major reaction product. The unexpected formation of pyrrolidin-1-ium formate as intermediate of the reaction the 1-catalyzed of CO with pyrrolidine and HSiMePh has been observed, and its role in the formation of 1-formylpyrrolidine rationalized. Moreover, a mechanism for the reaction of CO with hydrosilanes, in the presence and in the absence of amines, based on theoretical calculations has been proposed., The authors express their appreciation for the financial support from MICINN/FEDER projects PGC2018‐099383‐B‐100 and CTQ2016‐75884‐P, and the Regional Government of Aragón/FEDER 2014‐2020 “Building Europe from Aragón” (group E42_17R). J.M. acknowledges the financial support provided by the Spanish “Ministerio de Ciencia, Innovación y Universidades” (FPU14/06003). In addition, the resources from the supercomputer “Memento”, technical expertise and assistance provided by BIFIZCAM (Universidad de Zaragoza) are acknowledged.

The zwitterionic compound [Cp*RhCl{(MeIm)2CHCOO}] is an efficient catalyst for the hydrosilylation of terminal alkynes with excellent regio- and stereoselectivity toward the less thermodynamically stable β-(Z)-vinylsilane isomer under mild reaction conditions. A broad range of linear 1-alkynes, cycloalkyl acetylenes, and aromatic alkynes undergo the hydrosilylation with HSiMe2Ph to afford the corresponding β-(Z)-vinylsilanes in quantitative yields in short reaction times. The reaction of aliphatic alkynes with HSiEt3 is slower, resulting in a slight decrease of selectivity toward the β-(Z)-vinylsilane product, which is still greater than 90%. However, a significant selectivity decrease is observed in the hydrosilylation of aromatic alkynes because of the β-(Z) → β-(E) vinylsilane isomerization. Moreover, the hydrosilylation of bulky alkynes, such as t-Bu–C≡CH or Et3SiC≡CH, is unselective. Experimental evidence suggests that the carboxylate function plays a key role in the reaction mechanism, which has been validated by means of density functional theory calculations, as well as by mass spectrometry and labeling studies. On the basis of previous results, we propose an ionic outer-sphere mechanism pathway in which the carboxylate fragment acts as a silyl carrier. Namely, the hydrosilylation mechanism entails the heterolytic activation of the hydrosilane assisted by the carboxylate function to give the hydrido intermediate [Cp*RhH{(MeIm)2CHCOO–SiR3}]+. The transference of the silylium moiety from the carboxylate to the alkyne results in the formation of a flat β-silyl carbocation intermediate that undergoes a hydride transfer from the Rh(III) center to generate the vinylsilane product. The outstanding β-(Z) selectivity results from the minimization of the steric interaction between the silyl moiety and the ligand system in the hydride transfer transition state., The authors express their appreciation for the financial support from the Spanish Ministry of Economy and Competitiveness MINECO/FEDER under the project CTQ2016-75884-P and the Regional Governments of Aragón/FEDER 2014–2020 “Building Europe from Aragón” (group E42_17R). In addition, the resources from the supercomputer “Memento,” technical expertise, and assistance provided by BIFIZCAM (Universidad de Zaragoza) are acknowledged.

The bis-imidazolium salt, 1,1-bis(N-methylimidazolium) acetate bromide, is a convenient precursor for the synthesis of zwitterionic iridium(I) [Ir(cod){(MeIm)2CHCOO}] and cationic iridium(III) [IrH(cod){(MeIm)2CHCOO}]+ compounds (MeIm = 3-methylimidazol-2-yliden-1-yl) having a carboxylate-functionalized bis(NHC) ligand. The [Ir(cod){(MeIm)2CHCOO}] compound catalyzes the hydrogenation of CO2 to formate in water using NEt3 as base, reaching turnover numbers of approximately 1500. Reactivity studies have shown that activation of the catalyst precursor involves the reaction with H2 in a multistep process that under catalytic conditions results in the formation of a dihydrido iridium(III) octahedral [IrH2(H2O){(MeIm)2CHCOO}] species stabilized by the κ3-C,C′,O coordination of the ligand. DFT studies on the mechanism were carried out to elucidate two possible roles of the base. In the first one, NEt3 neutralizes only the produced formic acid, whereas in the second it assists the proton transfer in heterolytic cleavage of the H2 molecule. Although this base-involved mechanism is more favorable in that it exhibits a lower energy span for the overall reaction, the energy barrier obtained from kinetic experiments suggests that both mechanisms could be operative under the experimental reaction conditions., Financial support from the Ministerio de Economía y Competitividad (MINECO/FEDER) of Spain (Projects CTQ2013-42532-P and CTQ2016-75884-P) and Diputación General de Aragón (DGA/FSE E07) is gratefully acknowl-edged. R. P-O. acknowledges her fellowship from MINECO (BES-2011-045364, EEBB-I-14-08939 and EEBB-I-15-10125). Additional support from the DFG (Cluster of Excellence “Tailor-made Fuels from Biomass”, which is funded by the Excellence initiative by the German Federal and State Governments to promote science and research at German universities) is gratefully acknowledged.

Zwitterionic water-soluble [Cp*IrIIICl{(MeIm)2CHCOO}] and [IrI(cod){(MeIm)2CHCOO}] complexes featuring a carboxylate bridge-functionalized bis-N-heterocyclic carbene ligand efficiently catalyzed water oxidation using ammonium cerium(IV) nitrate (CAN) or sodium periodate as sacrificial oxidants. Excellent yields with TOF50 numbers up to 1000 h−1 have been achieved using CAN as electron acceptor at [CAN]/[Ir] ratios higher than 700. The investigation of the reaction mechanism by UV-vis seems to evidence that both catalyst precursors are transformed into the same active molecular species resulting from the degradation of the hydrocarbon ligands which is partially supported by the similarity of the oxygen evolution profiles at moderate oxidant/catalyst ratios for both catalyst precursors and the same chemical oxidant. In addition, DLS studies provide evidence for the participation of homogeneous iridium molecular species as intermediates likely stabilized by the carboxylate-functionalized bis-NHC ligand., Financial support from the Spanish Ministry of Economy and Competitiveness (MINECO/FEDER, Projects CTQ2013-42532-P and CTQ2016-75884-P), and Diputación General de Aragón (DGA/FSE E42_17R) is gratefully acknowledged. R. P.-O. thanks MINECO for a predoctoral fellowship (BES-2011-045364)., We acknowledge support of the publication fee by the CSIC Open Access Support Initiative through its Unit of Information Resources for Research (URICI)

A series of water-soluble zwitterionic complexes featuring a carboxylate bridge-functionalized bis-N-heterocyclic carbene ligand of formula [Cp MCl{(MeIm)CHCOO}] and [M(diene){(MeIm)CHCOO}] (Cp∗ = 1,2,3,4,5-pentamethylcyclopentadienyl; M = Rh, Ir; MeIm = 3-methylimidazol-2-yliden-1-yl; diene = 1,5-cyclooctadiene (cod), norbornadiene (nbd)) were prepared from the salt [(MeImH)CHCOO]Br and suitable metal precursor. The solid-state structure of both types of complexes shows a boat-shaped six-membered metallacycle derived of the κC,C′ coordination mode of the bis-NHC ligand. The uncoordinated carboxylate fragment is found at the bowsprit position in the Cp M complexes, whereas in the M(diene) complexes it is at the flagpole position of the metallacycle. The complexes [Rh(diene){(MeIm)CHCOO}] (diene = cod, nbd) exist as two conformational isomers in dichloromethane, bowsprit and flagpole, that interconvert through the boat-to-boat inversion of the metallacycle. An inversion barrier of ∼17 kcal·mol was determined by two-dimensional exchange spectroscopy NMR measurements for [Rh(cod){(MeIm)CHCOO}]. Reaction of zwitterionic Cp M complexes with methyl triflate or tetrafluoroboric acid affords the cationic complexes [Cp MCl{(MeIm)CHCOOMe}] or [Cp MCl{(MeIm)CHCOOH}] (M = Rh, Ir) featuring carboxy and methoxycarbonyl functionalized methylene-bridged bis-NHC ligands, respectively. Similarly, complexes [M(diene){(MeIm)CHCOOMe}] (M = Rh, Ir) were prepared by alkylation of the corresponding zwitterionic M(diene) complexes with methyl triflate. In contrast, reaction of [Ir(cod){(MeIm)CHCOO}] with HBF·EtO (Et = ethyl), CHOTf, CHI, or I gives cationic iridium(III) octahedral complexes [IrX(cod){(MeIm)CHCOO}] (X = H, Me, or I) featuring a tripodal coordination mode of the carboxylate bridge-functionalized bis-NHC ligand. The switch from κC,C′ to κC,C′,O coordination of the bis-NHC ligand accompanying the oxidative addition prevents the coordination of the anions eventually formed in the process that remain as counterions., Financial support from the Spanish Ministry of Economy and Competitiveness (MINECO/FEDER) under the Project CTQ2016-75884-P and the Diputación General de Aragón (DGA/FSE-E07) is gratefully acknowledged. R.P.-O. also thanks MINECO for a predoctoral fellowship (BES-2011-045364).

The catalytic activity in the hydrosilylation of terminal alkynes by the unsaturated hydrido iridium(III) compound [IrH(κ-hqca)(coe)] (1), which contains the rigid asymmetrical dianionic ONO pincer ligand 8-oxidoquinoline-2-carboxylate, has been studied. A range of aliphatic and aromatic 1-alkynes has been efficiently reduced using various hydrosilanes. Hydrosilylation of the linear 1-alkynes hex-1-yne and oct-1-yne gives a good selectivity toward the β-(Z)-vinylsilane product, while for the bulkier t-Bu-C≡CH a reverse selectivity toward the β-(E)-vinylsilane and significant amounts of alkene, from a competitive dehydrogenative silylation, has been observed. Compound 1, unreactive toward silanes, reacts with a range of terminal alkynes RC≡CH, affording the unsaturated η-alkenyl complexes [Ir(κ-hqca)(E-CH=CHR)(coe)] in good yield. These species are able to coordinate monodentate neutral ligands such as PPh and pyridine, or CO in a reversible way, to yield octahedral derivatives. Further mechanistic aspects of the hydrosilylation process have been studied by DFT calculations. The catalytic cycle passes through Ir(III) species with an iridacyclopropene (η-vinylsilane) complex as the key intermediate. It has been found that this species may lead both to the dehydrogenative silylation products, via a β-elimination process, and to a hydrosilylation cycle. The β-elimination path has a higher activation energy than hydrosilylation. On the other hand, the selectivity to the vinylsilane hydrosilylation products can be accounted for by the different activation energies involved in the attack of a silane molecule at two different faces of the iridacyclopropene ring to give η-vinylsilane complexes with either an E or Z configuration. Finally, proton transfer from a η-silane to a η-vinylsilane ligand results in the formation of the corresponding β-(Z)- and β-(E)-vinylsilane isomers, respectively., Financial support from the Ministerio de Economia y Competitividad (MINECO/FEDER) of Spain (Project CTQ2013-42532-P) and Diputación General de Aragón (DGA/FSE E07) is gratefully acknowledged. R.P.-O. acknowledges her fellowship from the MINECO (BES-2011-045364).