Parkinson's disease (PD) is an aging-associated neurodegenerative disease affecting millions worldwide. Misfolding, oligomerization and accumulation of the human α-synuclein protein is a key ...pathological hallmark of PD and is associated with the progressive loss of dopaminergic neurons over the course of aging. Lifespan extension via the suppression of IGF-1/insulin-like signaling (IIS) offers a possibility to retard disease onset through induction of metabolic changes that provide neuroprotection. The nceh-1 gene of Caenorhabditis elegans encodes an ortholog of neutral cholesterol ester hydrolase 1 (NCEH-1), an IIS downstream protein that was identified in a screen as a modulator of α-synuclein accumulation in vivo. The mechanism whereby cholesterol metabolism functionally impacts neurodegeneration induced by α-synuclein is undefined. Here we report that NCEH-1 protects dopaminergic neurons from α-synuclein-dependent neurotoxicity in C. elegans via a mechanism that is independent of lifespan extension. We discovered that the presence of cholesterol, LDLR-mediated cholesterol endocytosis, and cholesterol efflux are all essential to NCEH-1-mediated neuroprotection. In protecting from α-synuclein neurotoxicity, NCEH-1 also stimulates cholesterol-derived neurosteroid formation and lowers cellular reactive oxygen species in mitochondria. Collectively, this study augments our understanding of how cholesterol metabolism can modulate a neuroprotective mechanism that attenuates α-synuclein neurotoxicity, thereby pointing toward regulation of neuronal cholesterol turnover as a potential therapeutic avenue for PD.
Allele-specific distinctions in the human apolipoprotein E (
) locus represent the best-characterized genetic predictor of Alzheimer's disease (AD) risk. Expression of isoform
ε2 is associated with ...reduced risk, while
ε3 is neutral and
ε4 carriers exhibit increased susceptibility. Using
, we generated a novel suite of humanized transgenic nematodes to facilitate neuronal modeling of amyloid-beta peptide (Aβ) co-expression in the context of distinct human
alleles. We found that co-expression of human
ε2 with Aβ attenuated Aβ-induced neurodegeneration, whereas expression of the
ε4 allele had no effect on neurodegeneration, indicating a loss of neuroprotective capacity. Notably, the
ε3 allele displayed an intermediate phenotype; it was not neuroprotective in young adults but attenuated neurodegeneration in older animals. There was no functional impact from the three
isoforms in the absence of Aβ co-expression. Pharmacological treatment that examined neuroprotective effects of
alleles on calcium homeostasis showed allele-specific responses to changes in ER-associated calcium dynamics in the Aβ background. Additionally, Aβ suppressed survival, an effect that was rescued by
ε2 and
ε3, but not
ε4. Expression of the
alleles in neurons, independent of Aβ, exerted no impact on survival. Taken together, these results illustrate that
provides a powerful
platform with which to explore how AD-associated neuronal pathways are modulated by distinct
gene products in the context of Aβ-associated neurotoxicity. The significance of both ApoE and Aβ to AD highlights the utility of this new pre-clinical model as a means to dissect their functional inter-relationship.This article has an associated First Person interview with the first author of the paper.
The AAA+ protein disaggregase, Hsp104, increases fitness under stress by reversing stress-induced protein aggregation. Natural Hsp104 variants might exist with enhanced, selective activity against ...neurodegenerative disease substrates. However, natural Hsp104 variation remains largely unexplored. Here, we screened a cross-kingdom collection of Hsp104 homologs in yeast proteotoxicity models. Prokaryotic ClpG reduced TDP-43, FUS, and α-synuclein toxicity, whereas prokaryotic ClpB and hyperactive variants were ineffective. We uncovered therapeutic genetic variation among eukaryotic Hsp104 homologs that specifically antagonized TDP-43 condensation and toxicity in yeast and TDP-43 aggregation in human cells. We also uncovered distinct eukaryotic Hsp104 homologs that selectively antagonized α-synuclein condensation and toxicity in yeast and dopaminergic neurodegeneration in
. Surprisingly, this therapeutic variation did not manifest as enhanced disaggregase activity, but rather as increased passive inhibition of aggregation of specific substrates. By exploring natural tuning of this passive Hsp104 activity, we elucidated enhanced, substrate-specific agents that counter proteotoxicity underlying neurodegeneration.
Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, collectively referred to as synucleinopathies, are associated with a diverse group of genetic and environmental ...susceptibilities. The best studied of these is PD. alpha-Synuclein (alpha-syn) has a key role in the pathogenesis of both familial and sporadic PD, but evidence linking it to other predisposition factors is limited. Here we report a strong genetic interaction between alpha-syn and the yeast ortholog of the PD-linked gene ATP13A2 (also known as PARK9). Dopaminergic neuron loss caused by alpha-syn overexpression in animal and neuronal PD models is rescued by coexpression of PARK9. Further, knockdown of the ATP13A2 ortholog in Caenorhabditis elegans enhances alpha-syn misfolding. These data provide a direct functional connection between alpha-syn and another PD susceptibility locus. Manganese exposure is an environmental risk factor linked to PD and PD-like syndromes. We discovered that yeast PARK9 helps to protect cells from manganese toxicity, revealing a connection between PD genetics (alpha-syn and PARK9) and an environmental risk factor (PARK9 and manganese). Finally, we show that additional genes from our yeast screen, with diverse functions, are potent modifiers of alpha-syn-induced neuron loss in animals, establishing a diverse, highly conserved interaction network for alpha-syn.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Parkinson's disease (PD), the second most common neurodegenerative disease, is characterised by the motor symptoms of bradykinesia, rigidity and resting tremor and non-motor symptoms of sleep ...disturbances, constipation, and depression. Pathological hallmarks include neuroinflammation, degeneration of dopaminergic neurons in the substantia nigra pars compacta, and accumulation of misfolded α-synuclein proteins as intra-cytoplasmic Lewy bodies and neurites. Microglia and astrocytes are essential to maintaining homeostasis within the central nervous system (CNS), including providing protection through the process of gliosis. However, dysregulation of glial cells results in disruption of homeostasis leading to a chronic pro-inflammatory, deleterious environment, implicated in numerous CNS diseases. Recent evidence has demonstrated a role for peripheral immune cells, in particular T lymphocytes in the pathogenesis of PD. These cells infiltrate the CNS, and accumulate in the substantia nigra, where they secrete pro-inflammatory cytokines, stimulate surrounding immune cells, and induce dopaminergic neuronal cell death. Indeed, a greater understanding of the integrated network of communication that exists between glial cells and peripheral immune cells may increase our understanding of disease pathogenesis and hence provide novel therapeutic approaches.
The societal burden presented by Alzheimer’s disease warrants both innovative and expedient means by which its underlying molecular causes can be both identified and mechanistically exploited to ...discern novel therapeutic targets and strategies. The conserved characteristics, defined neuroanatomy, and advanced technological application of Caenorhabditis elegans render this metazoan an unmatched tool for probing neurotoxic factors. In addition, its short lifespan and importance in the field of aging make it an ideal organism for modeling age-related neurodegenerative disease. As such, this nematode system has demonstrated its value in predicting functional modifiers of human neurodegenerative disorders. Here, we review how C. elegans has been utilized to model Alzheimer’s disease. Specifically, we present how the causative neurotoxic peptides, amyloid-β and tau, contribute to disease-like neurodegeneration in C. elegans and how they translate to human disease. Furthermore, we describe how a variety of transgenic animal strains, each with distinct utility, have been used to identify both genetic and pharmacological modifiers of toxicity in C. elegans. As technological advances improve the prospects for intervention, the rapidity, unparalleled accuracy, and scale that C. elegans offers researchers for defining functional modifiers of neurodegeneration should speed the discovery of improved therapies for Alzheimer’s disease.
It has been theorized that physical literacy is associated with physical activity and health. The purpose of this study is to investigate the associations between physical literacy and health, and if ...this relationship is mediated by moderate-to-vigorous physical activity (MVPA). Two hundred and twenty-two children (113 girls, 10.7 ± 1.0 years old) participated in this cross-sectional study. A physical literacy composite score was computed from measures of PLAYfun, PLAYparent, and PLAYself. Physical activity was measured over seven days with accelerometers, expressed as MVPA (min/day). Health indicators included: body composition (percent body fat), aerobic fitness (treadmill time and 60s heart rate recovery), resting systolic blood pressure, and quality of life. Physical literacy was significantly associated (p < 0.001) with percent body fat (R2 = 0.23), treadmill time (R2 = 0.21), 60 s heart rate recovery (R2 = 0.36), systolic blood pressure (R2 = 0.11), and quality of life (R2 = 0.11). The relationships between physical literacy and aerobic fitness, but not other health indicators, were directly mediated by MVPA. Higher physical literacy in children is associated with favorable health indicators, and the relationships between physical literacy and aerobic fitness were influenced by MVPA. Future work should examine these relationships longitudinally and determine if changes in physical literacy leads to changes in health.
We have been investigating the role that phosphatidylethanolamine (PE) and phosphatidylcholine (PC) content plays in modulating the solubility of the Parkinson's disease protein alpha-synuclein ...(α-syn) using Saccharomyces cerevisiae and Caenorhabditis elegans. One enzyme that synthesizes PE is the conserved enzyme phosphatidylserine decarboxylase (Psd1/yeast; PSD-1/worms), which is lodged in the inner mitochondrial membrane. We previously found that decreasing the level of PE due to knockdown of Psd1/psd-1 affects the homeostasis of α-syn in vivo. In S. cerevisiae, the co-occurrence of low PE and α-syn in psd1Δ cells triggers mitochondrial defects, stress in the endoplasmic reticulum, misprocessing of glycosylphosphatidylinositol-anchored proteins, and a 3-fold increase in the level of α-syn. The goal of this study was to identify drugs that rescue this phenotype. We screened the Prestwick library of 1121 Food and Drug Administration-approved drugs using psd1Δ + α-syn cells and identified cyclosporin A, meclofenoxate hydrochloride, and sulfaphenazole as putative protective compounds. The protective activity of these drugs was corroborated using C. elegans in which α-syn is expressed specifically in the dopaminergic neurons, with psd-1 depleted by RNAi. Worm populations were examined for dopaminergic neuron survival following psd-1 knockdown. Exposure to cyclosporine, meclofenoxate, and sulfaphenazole significantly enhanced survival at day 7 in α-syn-expressing worm populations whereby 50-55% of the populations displayed normal neurons, compared to only 10-15% of untreated animals. We also found that all three drugs rescued worms expressing α-syn in dopaminergic neurons that were deficient in the phospholipid cardiolipin following cardiolipin synthase (crls-1) depletion by RNAi. We discuss how these drugs might block α-syn pathology in dopaminergic neurons.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Retromer is a protein assembly that plays a central role in orchestrating export of transmembrane-spanning cargo proteins from endosomes into retrieval pathways destined for the Golgi apparatus and ...the plasma membrane 1. Recently, a specific mutation in the retromer component VPS35, VPS35(D620N), has linked retromer dysfunction to familial autosomal dominant and sporadic Parkinson disease 2, 3. However, the effect of this mutation on retromer function remains poorly characterized. Here we established that in cells expressing VPS35(D620N) there is a perturbation in endosome-to-TGN transport but not endosome-to-plasma membrane recycling, which we confirm in patient cells harboring the VPS35(D620N) mutation. Through comparative stable isotope labeling by amino acids in cell culture (SILAC)-based analysis of wild-type VPS35 versus the VPS35(D620N) mutant interactomes, we establish that the major defect of the D620N mutation lies in the association to the actin-nucleating Wiskott-Aldrich syndrome and SCAR homolog (WASH) complex. Moreover, using isothermal calorimetry, we establish that the primary defect of the VPS35(D620N) mutant is a 2.2 ± 0.5-fold decrease in affinity for the WASH complex component FAM21. These data define the primary molecular defect in retromer assembly that arises from the VPS35(D620N) mutation and, by revealing functional effects on retromer-mediated endosome-to-TGN transport, provide new insight into retromer deregulation in Parkinson disease.
•VPS35(D620N) mutation leads to a defect in endosome-to-TGN transport•Mutant has a perturbed association with the actin-polymerizing WASH complex•Primary defect is a reduced affinity for binding WASH component FAM21•Provides new molecular insight into retromer deregulation in Parkinson disease
Using quantitative proteomics and functional analysis in patient-derived fibroblasts, McGough et al. define the primary molecular defect associated with the Parkinson disease-linked retromer VPS35(D620N) mutation and, by revealing effects on retromer-mediated endosome-to-TGN transport, provide new insight into retromer deregulation in this disease.
PDF
