Parkinson's disease (PD), an adult neurodegenerative disorder, has been clinically linked to the lysosomal storage disorder Gaucher disease (GD), but the mechanistic connection is not known. Here, we ...show that functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of α-synuclein (α-syn), and results in neurotoxicity through aggregation-dependent mechanisms. Glucosylceramide (GlcCer), the GCase substrate, directly influenced amyloid formation of purified α-syn by stabilizing soluble oligomeric intermediates. We further demonstrate that α-syn inhibits the lysosomal activity of normal GCase in neurons and idiopathic PD brain, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies. These findings suggest that the bidirectional effect of α-syn and GCase forms a positive feedback loop that may lead to a self-propagating disease. Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies.
Display omitted
► Mechanistic link between Gaucher disease and synucleinopathies such as Parkinson's ► Lysosomal glucosylceramide accumulation in Gaucher stabilizes α-synuclein oligomers ► α-synuclein inhibits lysosomal trafficking of glucocerebrosidase in synucleinopathies ► Glucocerebrosidase may be a therapeutic target in synucleinopathies
A panel of experts was convened by the Infectious Diseases Society of America (IDSA) to update the 2004 clinical practice guideline on outpatient parenteral antimicrobial therapy (OPAT) 1. This ...guideline is intended to provide insight for healthcare professionals who prescribe and oversee the provision of OPAT. It considers various patient features, infusion catheter issues, monitoring questions, and antimicrobial stewardship concerns. It does not offer recommendations on the treatment of specific infections. The reader is referred to disease- or organism-specific guidelines for such support.
Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and ...focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data-driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC50 < 0.1 μg/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.
Display omitted
•Map 377 mAbs: 19 of 80 recognizing the RBD are potent neutralizers; 1 potent NTD binder•19 Fab-antigen complex structures; 80 mAbs mapped on RBD and clustered into 5 epitopes•Most potent mAbs are ACE2 blockers, neutralize with few ACE2s, some Fabs glycosylated•mAbs reveal unique examples of NTD binding, RBD binding mode, and LC optimization
Dejnirattisai et al. present an in-depth study of the human antibody response to SARS-CoV-2 infection. By characterizing 377 human mAbs from recovered COVID-19 patients, and determining 19 protein structures, they construct a map of antibody footprints on the RBD that describes in great detail its antigenic anatomy.
Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between ...impaired IGF-1/insulin-like signaling (IIS) and lifespan extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-associated genetic modifiers of α-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson’s disease. An outcome of this strategy was the identification of GPI-1/GPI, an enzyme in glucose metabolism, as a daf-2-regulated modifier that acts independent of the downstream cytoprotective transcription factor DAF-16/FOXO to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from α-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration.
Display omitted
•Insulin signaling modulates neurodegeneration in fly and worm Parkinson’s models•Reduced insulin-signaling screen reveals metabolic modifiers of protein misfolding•A glycolytic enzyme, GPI, is neuroprotective across worms, flies, and mouse neurons•GPI functions independently of DAF-16/FOXO to modulate proteostasis via glycolysis
Knight et al. screened for modifiers of α-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson’s disease, in worms with decreased IIS signaling. They identify the glycolytic enzyme GPI, which plays a conserved DAF-16/FOXO-independent role in worms, flies, and primary mouse neurons, integrating metabolic regulation with proteotoxicity and dopaminergic neurodegeneration.
The polycomb repressive complex 2 (PRC2) methylates lysine 27 of histone H3 (H3K27) through its catalytic subunit Ezh2. PRC2-mediated di- and tri-methylation (H3K27me2/H3K27me3) have been ...interchangeably associated with gene repression. However, it remains unclear whether these two degrees of H3K27 methylation have different functions. In this study, we have generated isogenic mouse embryonic stem cells (ESCs) with a modified H3K27me2/H3K27me3 ratio. Our findings document dynamic developmental control in the genomic distribution of H3K27me2 and H3K27me3 at regulatory regions in ESCs. They also reveal that modifying the ratio of H3K27me2 and H3K27me3 is sufficient for the acquisition and repression of defined cell lineage transcriptional programs and phenotypes and influences induction of the ESC ground state.
Display omitted
•H3K27me2/H3K27me3 are redistributed during ESC differentiation•H3K27 methylation recapitulates changes during differentiation in Ezh2-edited ESCs•In pluripotent culture conditions, Ezh2-edited ESCs activate the neurogenic program•Ezh2-edited ESCs are refractory to a 2i-medium-induced “ground state”
Juan et al. use genome editing to subtly modify H3K27 methylation states (H3K27me2/H3K27me3) and report that such perturbation influences the ability of ESCs to differentiate into preferential cell lineages and acquire a “ground state.”
A panel of experts was convened by the Infectious Diseases Society of America to update the 2004 clinical practice guideline on outpatient parenteral antimicrobial therapy (OPAT) 1. This guideline is ...intended to provide insight for healthcare professionals who prescribe and oversee the provision of OPAT. It considers various patient features, infusion catheter issues, monitoring questions, and antimicrobial stewardship concerns. It does not offer recommendations on the treatment of specific infections. The reader is referred to disease- or organism-specific guidelines for such support.
Genomic multiplication of the locus-encoding human α-synuclein (α-syn), a polypeptide with a propensity toward intracellular misfolding, results in Parkinson's disease (PD). Here we report the ...results from systematic screening of nearly 900 candidate genetic targets, prioritized by bioinformatic associations to existing PD genes and pathways, via RNAi knockdown. Depletion of 20 gene products reproducibly enhanced misfolding of α-syn over the course of aging in the nematode Caenorhabditis elegans. Subsequent functional analysis of seven positive targets revealed five previously unreported gene products that significantly protect against age- and dose-dependent α-syn-induced degeneration in the dopamine neurons of transgenic worms. These include two trafficking proteins, a conserved cellular scaffold-type protein that modulates G protein signaling, a protein of unknown function, and one gene reported to cause neurodegeneration in knockout mice. These data represent putative genetic susceptibility loci and potential therapeutic targets for PD, a movement disorder affecting ≈2% of the population over 65 years of age.
During the COVID-19 pandemic, genomics and bioinformatics have emerged as essential public health tools. The genomic data acquired using these methods have supported the global health response, ...facilitated the development of testing methods and allowed the timely tracking of novel SARS-CoV-2 variants. Yet the virtually unlimited potential for rapid generation and analysis of genomic data is also coupled with unique technical, scientific and organizational challenges. Here, we discuss the application of genomic and computational methods for efficient data-driven COVID-19 response, the advantages of the democratization of viral sequencing around the world and the challenges associated with viral genome data collection and processing.
Lysosomes are responsible for degradation and recycling of bulky cell material, including accumulated misfolded proteins and dysfunctional organelles. Increasing evidence implicates lysosomal ...dysfunction in several neurodegenerative disorders, including Parkinson's disease and related synucleinopathies, which are characterized by the accumulation of α-synuclein (α-syn) in Lewy bodies. Studies of lysosomal proteins linked to neurodegenerative disorders present an opportunity to uncover specific molecular mechanisms and pathways that contribute to neurodegeneration. Loss-of-function mutations in a lysosomal protein, ATP13A2 (PARK9), cause Kufor-Rakeb syndrome that is characterized by early-onset parkinsonism, pyramidal degeneration and dementia. While loss of ATP13A2 function plays a role in α-syn misfolding and toxicity, the normal function of ATP13A2 in the brain remains largely unknown. Here, we performed a screen to identify ATP13A2 interacting partners, as a first step toward elucidating its function. Utilizing a split-ubiquitin membrane yeast two-hybrid system that was developed to identify interacting partners of full-length integral membrane proteins, we identified 43 novel interactors that primarily implicate ATP13A2 in cellular processes such as endoplasmic reticulum (ER) translocation, ER-to-Golgi trafficking and vesicular transport and fusion. We showed that a subset of these interactors modified α-syn aggregation and α-syn-mediated degeneration of dopaminergic neurons in Caenorhabditis elegans, further suggesting that ATP13A2 and α-syn are functionally linked in neurodegeneration. These results implicate ATP13A2 in vesicular trafficking and provide a platform for further studies of ATP13A2 in neurodegeneration.
Care home residents have high rates of hospital admission. The UK National Early Warning Score (NEWS2) standardizes the secondary care response to acute illness. However, the ability of NEWS2 to ...predict adverse health outcomes specifically for care home residents is unknown. This study explored the relationship between NEWS2 on admission to hospital and resident outcome 7 days later.
Repeated cross-sectional study.
Data on UK care home residents admitted to 160 hospitals in two 24-hour periods (2019 and 2020).
Chi-squared and Kruskal-Wallis tests, and multinomial regression were used to explore the association between low (score ≤2), intermediate (3–4), high (5–6), and critically high (≥7) NEWS2 on admission and each of the following: discharge on day of admission, admission and discharge within 7 days, prolonged hospital admission (>7 days), and death.
From 665 resident admissions across 160 hospital sites, NEWS2 was low for 54%, intermediate for 18%, high for 13%, and critically high for 16%. The 7-day outcome was 10% same-day discharge, 47% admitted and subsequently discharged, 34% remained inpatients, and 8% died. There is a significant association between NEWS2 and these outcomes (P < .001). Compared with those with low NEWS2, residents with high and critically high NEWS2 had 3.6 and 9.5 times increased risk of prolonged hospitalization relative risk ratio (RRR) 3.56; 95% CI 1.02–12.37; RRR 9.47; CI 2.20–40.67, respectively. The risk of death was approximately 14 times higher for residents with high NEWS2 (RRR 13.62; CI 3.17–58.49) and 54 times higher (RRR 53.50; CI 11.03–259.54) for critically high NEWS2.
Higher NEWS2 measurements on admission are associated with an increased risk of hospitalization up to 7 days duration, prolonged admission, and mortality for care home residents. NEWS2 may have a role as an adjunct to acute care decision making for hospitalized residents.
PDF
