Astrocytes are the most populous glial subtype and are critical for brain function. Despite this, historically there have been few studies into the role that they may have in neurodegenerative ...diseases, such as Parkinson’s disease (PD). Recently, however, several studies have determined that genes known to have a causative role in the development of PD are expressed in astrocytes and have important roles in astrocyte function. Here, we review these recent developments and discuss their impact on our understanding of the pathophysiology of PD, and the implications that this might have for its treatment.
Parkinson's disease (PD) is the second most common neurodegenerative disorder and a central role for α-synuclein (αSyn; SNCA) in disease aetiology has been proposed based on genetics and ...neuropathology. To better understand the pathological mechanisms of αSyn, we generated induced pluripotent stem cells (iPSCs) from healthy individuals and PD patients carrying the A53T SNCA mutation or a triplication of the SNCA locus and differentiated them into dopaminergic neurons (DAns). iPSC-derived DAn from PD patients carrying either mutation showed increased intracellular αSyn accumulation, and DAns from patients carrying the SNCA triplication displayed oligomeric αSyn pathology and elevated αSyn extracellular release. Transcriptomic analysis of purified DAns revealed perturbations in expression of genes linked to mitochondrial function, consistent with observed reduction in mitochondrial respiration, impairment in mitochondrial membrane potential, aberrant mitochondrial morphology and decreased levels of phosphorylated DRP1Ser616. Parkinson's iPSC-derived DAns showed increased endoplasmic reticulum stress and impairments in cholesterol and lipid homeostasis. Together, these data show a correlation between αSyn cellular pathology and deficits in metabolic and cellular bioenergetics in the pathology of PD.
Non-neuronal cell types such as astrocytes can contribute to Parkinson's disease (PD) pathology. The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is one of the most common known causes of ...familial PD. To characterize its effect on astrocytes, we developed a protocol to produce midbrain-patterned astrocytes from human induced pluripotent stem cells (iPSCs) derived from PD LRRK2 G2019S patients and healthy controls. RNA sequencing analysis revealed the downregulation of genes involved in the extracellular matrix in PD cases. In particular, transforming growth factor beta 1 (TGFB1), which has been shown to inhibit microglial inflammatory response in a rat model of PD, and matrix metallopeptidase 2 (MMP2), which has been shown to degrade α-synuclein aggregates, were found to be down-regulated in LRRK2 G2019S astrocytes. Our findings suggest that midbrain astrocytes carrying the LRRK2 G2019S mutation may have reduced neuroprotective capacity and may contribute to the development of PD pathology.
•Genome-wide RNA sequencing profiling of LRRK2 G2019S iPSC-derived astrocytes.•The extracellular matrix is perturbed in LRRK2 G2019S iPSC-astrocytes.•MMP2 and TGFB1 are down-regulated in the presence of the LRRK2 G2019S mutation.•Reduced neuroprotective potential of astrocytes may contribute to PD pathology.
The H1 haplotype of the microtubule-associated protein tau (MAPT) locus is genetically associated with neurodegenerative diseases, including Parkinson's disease (PD), and affects gene expression and ...splicing. However, the functional impact on neurons of such expression differences has yet to be fully elucidated. Here, we employ extended maturation phases during differentiation of induced pluripotent stem cells (iPSCs) into mature dopaminergic neuronal cultures to obtain cultures expressing all six adult tau protein isoforms. After 6 months of maturation, levels of exon 3+ and exon 10+ transcripts approach those of adult brain. Mature dopaminergic neuronal cultures display haplotype differences in expression, with H1 expressing 22% higher levels of MAPT transcripts than H2 and H2 expressing 2-fold greater exon 3+ transcripts than H1. Furthermore, knocking down adult tau protein variants alters axonal transport velocities in mature iPSC-derived dopaminergic neuronal cultures. This work links haplotype-specific MAPT expression with a biologically functional outcome relevant for PD.
•iPSC-derived dopaminergic neurons express six adult tau isoforms after 6 months•Mature dopaminergic neuronal cultures show haplotype differences in MAPT expression•Tau isoform expression is affected by both common and rare genetic variation•Knockdown of tau variants alters axonal transport in dopaminergic neuronal cultures
In this article, Caffrey, Wade-Martins, and colleagues show extended maturation of dopaminergic neuronal cultures gives expression of six adult tau isoforms displaying MAPT haplotype-specific differences in expression. Further, knocking down adult tau protein variants alters axonal transport velocities in mature iPSC-derived dopaminergic neuronal cultures, linking haplotype-specific MAPT expression with a biologically functional outcome relevant for PD.
Summary Background HLA-DRB1*15 genotype, previous infection with Epstein-Barr virus, and vitamin D insufficiency are susceptibility factors for multiple sclerosis, but whether they act ...synergistically to increase risk is unknown. We aimed to assess the contributions of these risk factors and the effect of established precursors of multiple sclerosis, such as brain lesions on MRI and oligoclonal bands in CSF at the time of incident demyelination, on development of multiple sclerosis in children. Methods In our prospective national cohort study, we assessed children who presented with incident CNS demyelination to any of the 16 paediatric health-care facilities or seven regional health-care facilities in Canada. We did univariate and multivariable analyses to assess contributions of HLA-DRB1*15 , Epstein-Barr virus, vitamin D status, MRI evidence of brain lesions, and CSF oligoclonal bands as determinants of multiple sclerosis. We used classification and regression tree analyses to generate a risk stratification algorithm for clinical use. Findings Between Sept 1, 2004, and June 30, 2010, we screened 332 children of whom 302 (91%) were eligible and followed-up for a median of 3·14 years (IQR 1·61–4·51). 63 (21%) children were diagnosed with multiple sclerosis after a median of 127 days (99–222). Although the risk of multiple sclerosis was increased with presence of one or more HLA-DRB1*15 alleles (hazard ratio HR 2·32, 95% CI 1·25–4·30), reduced serum 25-hydroxyvitamin D concentration (HR per 10 nmol/L decrease 1·11, 1·00–1·25), and previous Epstein-Barr-virus infection (HR 2·04, 0·99–4·20), no interactions between these variables were detected on multivariate analysis. Multiple sclerosis was strongly associated with baseline MRI evidence of one or more brain lesion (HR 37·9, 5·26–273·85) or CSF oligoclonal bands (6·33, 3·35–11·96), suggesting established disease. One patient diagnosed with multiple sclerosis had a normal MRI scan, and therefore sensitivity of an abnormal MRI scan for multiple sclerosis diagnosis was 98·4%. Interpretation Risk of multiple sclerosis in children can be stratified by presence of HLA-DRB1*15 alleles, remote Epstein-Barr virus infection, and low serum 25-hydroxyvitamin D concentrations. Similar to previous studies in adults, brain lesions detected on MRI and CSF oligoclonal bands in children are probable precursors to the clinical onset of multiple sclerosis. Children with a normal MRI are very likely to have a monophasic illness. Funding Canadian Multiple Sclerosis Scientific Research Foundation.
To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America ...(MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension.
Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study.
A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected.
Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population.
REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624.
This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo.
Summary Background Hyperglycaemia could substantially increase the risk of ischaemic heart disease in patients with type 2 diabetes. We investigated whether intensive lowering of glucose ...concentrations affects risk. Methods We assessed 10 251 adults aged 40–79 years with established type 2 diabetes, mean glycated haemoglobin A1c (HbA1c ) concentration of 67 mmol/mol (8·3%), and risk factors for ischaemic heart disease enrolled in the ACCORD trial. Participants were assigned to intensive or standard therapy (target HbA1c less than 42 or 53–63 mmol/mol less than 6·0% or 7·0–7·9%, respectively). We assessed fatal or non-fatal myocardial infarction, coronary revascularisation, unstable angina, and new angina during active treatment (mean 3·7 years) plus a further mean 1·2 years. This trial is registered with ClinicalTrials.gov , number NCT00000620. Findings Myocardial infarction was less frequent in the intensive than in the standard therapy group during active treatment (hazard ratio HR 0·80, 95% CI 0·67–0·96; p=0·015) and overall (0·84, 0·72–0·97; p=0·02). Findings were similar for combined myocardial infarction, coronary revascularisation, and unstable angina (active treatment HR 0·89, 95% CI 0·79–0·99, overall 0·87 0·79–0·96) and for coronary revascularisation alone (0·84, 0·75–0·94) and unstable angina alone (0·81, 0·67–0·97) during full follow-up. With lowest achieved HbA1C concentrations included as a time-dependent covariate, all hazards became non-significant. Interpretation Raised glucose concentration is a modifiable risk factor for ischaemic heart disease in middle-aged people with type 2 diabetes and other cardiovascular risk factors. Funding National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Eye Intitute, and Centers for Disease Control and Prevention.
Parkinson's disease (PD) is a common neurodegenerative disorder, characterised by preferential loss of ventral midbrain dopaminergic (vmDA) neurons in the substantia nigra pars compacta (SNc). The ...majority of PD cases have unknown aetiology; however, between 5-10% arise due to known genetic mutations, the most common of which are found in the LRRK2 gene. LRRK2 is expressed in neurons and glia in the human brain; therefore, cell-autonomous and/or non-cell autonomous effects may participate in LRRK2-mutation-mediated degeneration of vmDA neurons. This study set out to understand the effects of LRRK2 mutations on human vmDA neurons and midbrain astrocytes, and to shed new light on the mechanisms of PD pathogenesis. To achieve this goal, differentiation protocols were generated to produce vmDA neurons and midbrain patterned (MP) astrocytes from induced pluripotent stem cells (iPSCs). iPSCs from patients carrying the LRRK2-G2019S mutation were differentiated into both cell types, and hypothesis-driven analysis of cellular functions including autophagy, mitochondrial respiration, glycolysis, and cellular migration was conducted; however, no disease phenotypes were observed. Following this, proteomics and transcriptomics techniques were then used to analyse the effects of the LRRK2-G2019S mutation in an unbiased manner. In the iPSC-derived MPastrocyte cultures, this technique highlighted stochastic X-chromosome reactivation events that led to difficulties in interpreting the resulting data; however, in the iPSC-derived vmDA-neuron cultures, LRRK2-G2019S-mediated inhibition of endocytosis and axon guidance was identified. These findings were found to be consistent in iPSC-derived vmDA-neuron cultures carrying the LRRK2-R1441C mutation, suggesting that these two mutations exert their pathogenic effects through similar mechanisms. Finally, phosphoproteomics analysis of iPSC-derived vmDA-neuron cultures was conducted to identify bone fide LRRK2-kinase substrates. Eleven potential LRRK2- kinase substrates were identified, nine of which have been previously shown to participate in endocytic vesicle trafficking, neurite outgrowth, and synaptic function. The findings of this study suggest that LRRK2 has neuron-specific functions, and that its mutations contribute to neurodegeneration in a cell-autonomous manner.
Parkinson's disease (PD) is a common neurodegenerative disorder, characterised by preferential loss of ventral midbrain dopaminergic (vmDA) neurons in the substantia nigra pars compacta (SNc). The ...majority of PD cases have unknown aetiology; however, between 5-10% arise due to known genetic mutations, the most common of which are found in the LRRK2 gene. LRRK2 is expressed in neurons and glia in the human brain; therefore, cell-autonomous and/or non-cell autonomous effects may participate in LRRK2-mutation-mediated degeneration of vmDA neurons. This study set out to understand the effects of LRRK2 mutations on human vmDA neurons and midbrain astrocytes, and to shed new light on the mechanisms of PD pathogenesis. To achieve this goal, differentiation protocols were generated to produce vmDA neurons and midbrain patterned (MP) astrocytes from induced pluripotent stem cells (iPSCs). iPSCs from patients carrying the LRRK2-G2019S mutation were differentiated into both cell types, and hypothesis-driven analysis of cellular functions including autophagy, mitochondrial respiration, glycolysis, and cellular migration was conducted; however, no disease phenotypes were observed. Following this, proteomics and transcriptomics techniques were then used to analyse the effects of the LRRK2-G2019S mutation in an unbiased manner. In the iPSC-derived MPastrocyte cultures, this technique highlighted stochastic X-chromosome reactivation events that led to difficulties in interpreting the resulting data; however, in the iPSC-derived vmDA-neuron cultures, LRRK2-G2019S-mediated inhibition of endocytosis and axon guidance was identified. These findings were found to be consistent in iPSC-derived vmDA-neuron cultures carrying the LRRK2-R1441C mutation, suggesting that these two mutations exert their pathogenic effects through similar mechanisms. Finally, phosphoproteomics analysis of iPSC-derived vmDA-neuron cultures was conducted to identify bone fide LRRK2-kinase substrates. Eleven potential LRRK2- kinase substrates were identified, nine of which have been previously shown to participate in endocytic vesicle trafficking, neurite outgrowth, and synaptic function. The findings of this study suggest that LRRK2 has neuron-specific functions, and that its mutations contribute to neurodegeneration in a cell-autonomous manner.
Salt marshes buffer coastlines and provide critical ecosystem services from storm protection to food provision. Worldwide, these ecosystems are in danger of disappearing if they cannot increase ...elevation at rates that match sea-level rise. However, the magnitude of loss to be expected is not known. A synthesis of existing records of salt marsh elevation change was conducted in order to consider the likelihood of their future persistence. This analysis indicates that many salt marshes did not keep pace with sea-level rise in the past century and kept pace even less well over the past two decades. Salt marshes experiencing higher local sea-level rise rates were less likely to be keeping pace. These results suggest that sea-level rise will overwhelm most salt marshes’ capacity to maintain elevation. Under the most optimistic IPCC emissions pathway, 60% of the salt marshes studied will be gaining elevation at a rate insufficient to keep pace with sea-level rise by 2100. Without mitigation of greenhouse gas emissions this potential loss could exceed 90%, which will have substantial ecological, economic, and human health consequences.
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