Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease, whereas Gaucher disease (GD) is the most frequent lysosomal storage disorder caused by homozygous ...mutations in the glucocerebrosidase (GBA1) gene. Increased risk of developing PD has been observed in both GD patients and carriers. It has been estimated that GBA1 mutations confer a 20‐ to 30‐fold increased risk for the development of PD, and that at least 7–10% of PD patients have a GBA1 mutation. To date, mutations in the GBA1 gene constitute numerically the most important risk factor for PD. The type of PD associated with GBA1 mutations (PD‐GBA1) is almost identical to idiopathic PD, except for a slightly younger age of onset and a tendency to more cognitive impairment. Importantly, the pathology of PD‐GBA1 is identical to idiopathic PD, with nigral dopamine cell loss, Lewy bodies, and neurites containing alpha‐synuclein. The mechanism by which GBA1 mutations increase the risk for PD is still unknown. However, given that clinical manifestation and pathological findings in PD‐GBA1 patients are almost identical to those in idiopathic PD individuals, it is likely that, as in idiopathic PD, alpha‐synuclein accumulation, mitochondrial dysfunction, autophagic impairment, oxidative and endoplasmic reticulum stress may contribute to the development and progression of PD‐GBA1. Here, we review the GBA1 gene, its role in GD, and its link with PD.
The impact of glucocerebrosidase 1 (GBA1) mutations on functioning of endoplasmic reticulum (ER), lysosomes, and mitochondria. GBA1 mutations resulting in production of misfolded glucocerebrosidase (GCase) significantly affect the ER functioning. Misfolded GCase trapped in the ER leads to both an increase in the ubiquitin–proteasome system (UPS) and the ER stress. The presence of ER stress triggers the unfolded protein response (UPR) and/or endoplasmic reticulum‐associated degradation (ERAD). The prolonged activation of UPR and ERAD subsequently leads to increased apoptosis. The presence of misfolded GCase in the lysosomes together with a reduction in wild‐type GCase levels lead to a retardation of alpha‐synuclein degradation via chaperone‐mediated autophagy (CMA), which subsequently results in alpha‐synuclein accumulation and aggregation. Impaired lysosomal functioning also causes a decrease in the clearance of autophagosomes, and so their accumulation. GBA1 mutations perturb normal mitochondria functioning by increasing generation of free radical species (ROS) and decreasing adenosine triphosphate (ATP) production, oxygen consumption, and membrane potential. GBA1 mutations also lead to accumulation of dysfunctional and fragmented mitochondria.
This article is part of a special issue on Parkinson disease.
The impact of glucocerebrosidase 1 (GBA1) mutations on functioning of endoplasmic reticulum (ER), lysosomes, and mitochondria. GBA1 mutations resulting in production of misfolded glucocerebrosidase (GCase) significantly affect the ER functioning. Misfolded GCase trapped in the ER leads to both an increase in the ubiquitin–proteasome system (UPS) and the ER stress. The presence of ER stress triggers the unfolded protein response (UPR) and/or endoplasmic reticulum‐associated degradation (ERAD). The prolonged activation of UPR and ERAD subsequently leads to increased apoptosis. The presence of misfolded GCase in the lysosomes together with a reduction in wild‐type GCase levels lead to a retardation of alpha‐synuclein degradation via chaperone‐mediated autophagy (CMA), which subsequently results in alpha‐synuclein accumulation and aggregation. Impaired lysosomal functioning also causes a decrease in the clearance of autophagosomes, and so their accumulation. GBA1 mutations perturb normal mitochondria functioning by increasing generation of free radical species (ROS) and decreasing adenosine triphosphate (ATP) production, oxygen consumption, and membrane potential. GBA1 mutations also lead to accumulation of dysfunctional and fragmented mitochondria.
This article is part of a special issue on Parkinson disease.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
Gaucher disease is caused by mutations in the glucocerebrosidase 1 gene that result in deficiency of the lysosomal enzyme glucocerebrosidase. Both homozygous and heterozygous ...glucocerebrosidase 1 mutations confer an increased risk for developing Parkinson disease. Current estimates indicate that 10 to 25% of Parkinson patients carry glucocerebrosidase 1 mutations. Ambroxol is a small molecule chaperone that has been shown to increase glucocerebrosidase activity in vitro. This study investigated the effect of ambroxol treatment on glucocerebrosidase activity and on α‐synuclein and phosphorylated α‐synuclein protein levels in mice.
Methods
Mice were treated with ambroxol for 12 days. After the treatment, glucocerebrosidase activity was measured in the mouse brain lysates. The brain lysates were also analyzed for α‐synuclein and phosphorylated α‐synuclein protein levels.
Results
Ambroxol treatment resulted in increased brain glucocerebrosidase activity in (1) wild‐type mice, (2) transgenic mice expressing the heterozygous L444P mutation in the murine glucocerebrosidase 1 gene, and (3) transgenic mice overexpressing human α‐synuclein. Furthermore, in the mice overexpressing human α‐synuclein, ambroxol treatment decreased both α‐synuclein and phosphorylated α‐synuclein protein levels.
Interpretation
Our work supports the proposition that ambroxol should be further investigated as a potential novel disease‐modifying therapy for treatment of Parkinson disease and neuronopathic Gaucher disease to increase glucocerebrosidase activity and decrease α‐synuclein and phosphorylated α‐synuclein protein levels. Ann Neurol 2016;80:766–775
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Parkinson disease is the most common neurodegenerative movement disorder, estimated to affect one in twenty-five individuals over the age of 80. Mutations in glucocerebrosidase 1 (GBA1) represent the ...most common genetic risk factor for Parkinson disease. The link between GBA1 mutations and α-synuclein accumulation, a hallmark of Parkinson disease, is not fully understood. Following our recent finding that Gba1 mutations lead to increased α-synuclein accumulation in mice, we have studied the effects of a single injection of mouse α-synuclein pre-formed fibrils into the striatum of Gba1 mice that carry a L444P knock-in mutation. We found significantly greater formation and spread of α-synuclein inclusions in Gba1-transgenic mice compared to wild-type controls. This indicates that the Gba1 L444P mutation accelerates α-synuclein pathology and spread.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Atypical Hemolytic Uremic Syndrome Kavanagh, David; Goodship, Tim H.; Richards, Anna
Seminars in nephrology,
11/2013, Volume:
33, Issue:
6
Journal Article
Peer reviewed
Open access
Hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The atypical form of HUS is a disease characterized by complement ...overactivation. Inherited defects in complement genes and acquired autoantibodies against complement regulatory proteins have been described. Incomplete penetrance of mutations in all predisposing genes is reported, suggesting that a precipitating event or trigger is required to unmask the complement regulatory deficiency. The underlying genetic defect predicts the prognosis both in native kidneys and after renal transplantation. The successful trials of the complement inhibitor eculizumab in the treatment of atypical HUS will revolutionize disease management.
Context
Understanding the variability and dynamics of ecosystems, as well as their responses to climate or land use change, is challenging for policy makers and natural resource managers. Virtual ...reality (VR) can be used to render virtual landscapes as immersive, visceral experiences and communicate ecosystem dynamics to users in an effective and engaging way.
Objectives
To illustrate the potential and believability of VR, a team of landscape ecologists and immersive visualisation researchers modelled a reference Australian Box Gum Grassy Woodland landscape, an endangered eucalypt woodland ecosystem that is difficult to observe in its pre-European colonisation form.
Methods
We document considerations for designing the immersive virtual landscape, including the creation of animated three-dimensional (3D) plants that alternate between the seasons, and soundscapes that change through the course of a simulated day. We used a heuristic evaluation with experts to assess the potential of immersive VR landscape modeling.
Results
This cross disciplinary collaboration resulted in a VR experience that was evaluated in a series of meetings by 27 ecologists and managers in biodiversity conservation, many of whom were familiar with Box Gum Grassy Woodlands. 88% of participants stated that the simulation was believable and participants thought that virtual landscapes held great potential for education, public engagement and land management.
Conclusions
Possible future directions include open-source libraries of ecological 3D models, and the visual simulation of historic landscapes and future climate change scenarios.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Interleukin (IL)-6 family cytokines, such as IL-6 and IL-11, are defined by the shared use of the gp130 receptor for the downstream activation of STAT3 signaling and the activation of genes which ...contribute to the "hallmarks of cancer", including proliferation, survival, invasion and metastasis. Increased expression of these cytokines, or the ligand-specific receptors IL-6R and IL-11RA, in breast tumors positively correlate to disease progression and poorer patient outcome. In this review, we examine evidence from pre-clinical studies that correlate enhanced IL-6 and IL-11 mediated gp130/STAT3 signaling to the progression of breast cancer. Key processes by which the IL-6 family cytokines contribute to the heterogeneous nature of breast cancer, immune evasion and metastatic potential, are discussed. We examine the latest research into the therapeutic targeting of IL-6 family cytokines that inhibit STAT3 transcriptional activity as a potential breast cancer treatment, including current clinical trials. The importance of the IL-6 family of cytokines in cellular processes that promote the development and progression of breast cancer warrants further understanding of the molecular basis for its actions to help guide the development of future therapeutic targets.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Parkinson’s disease is a progressive neurodegenerative disorder, predominantly of the motor system. Although some genetic components and cellular mechanisms of Parkinson’s have been identified, much ...is still unknown. In recent years, emerging evidence has indicated that non-DNA-sequence variation (in particular epigenetic mechanisms) is likely to play a crucial role in the development and progression of the disease. Here, we present an up-to-date overview of epigenetic processes including DNA methylation, DNA hydroxymethylation, histone modifications and non-coding RNAs implicated in the brain of those with Parkinson’s disease. We will also discuss the limitations of current epigenetic research in Parkinson’s disease, the advantages of simultaneously studying genetics and epigenetics, and putative novel epigenetic therapies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Mutations in the glucocerebrosidase 1 (GBA1) gene are related to both Parkinson disease (PD) and Gaucher disease (GD). In both cases, the condition is associated with deficiency of glucocerebrosidase ...(GCase), the enzyme encoded by GBA1. Ambroxol is a small molecule chaperone that has been shown in mice to cross the blood‐brain barrier, increase GCase activity and reduce alpha‐synuclein protein levels. In this study, we analyze the effect of ambroxol treatment on GCase activity in healthy nonhuman primates. We show that daily administration of ambroxol results in increased brain GCase activity. Our work further indicates that ambroxol should be investigated as a novel therapy for both PD and neuronopathic GD in humans.
Treatment with 100 mg of ambroxol leads to approximately a 20% increase in brain glucocerebrosidase activity in a nonhuman primate.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Productivity of tree plantations is a function of the supply, capture and efficiency of use of resources, as outlined in the Production Ecology Equation. Species interactions in mixed-species stands ...can influence each of these variables. The importance of resource-use efficiency in determining forest productivity has been clearly demonstrated in monocultures; however, substantial knowledge gaps remain for mixtures. This review examines how the physiology and morphology of a given species can vary depending on whether it grows in a mixture or monoculture. We outline how physiological and morphological shifts within species, resulting from interactions in mixtures, may influence the three variables of the Production Ecology Equation, with an emphasis on nutrient resources nitrogen (N) and phosphorus (P). These include (i) resource availability, including soil nutrient mineralization, N₂ fixation and litter decomposition; (ii) proportion of resources captured, resulting from shifts in spatial, temporal and chemical patterns of root dynamics; (iii) resource-use efficiency. We found that more than 50% of mixed-species studies report a shift to greater above-ground nutrient content of species grown in mixtures compared to monocultures, indicating an increase in the proportion of resources captured from a site. Secondly, a meta-analysis showed that foliar N concentrations significantly increased for a given species in a mixture containing N₂-fixing species, compared to a monoculture, suggesting higher rates of photosynthesis and greater resource-use efficiency. Significant shifts in N- and P-use efficiencies of a given species, when grown in a mixture compared to a monoculture, occurred in over 65% of studies where resource-use efficiency could be calculated. Such shifts can result from changes in canopy photosynthetic capacities, changes in carbon allocation or changes to foliar nutrient residence times of species in a mixture. We recommend that future research focus on individual species' changes, particularly with respect to resource-use efficiency (including nutrients, water and light), when trees are grown in mixtures compared to monocultures. A better understanding of processes responsible for changes to tree productivity in mixed-species tree plantations can improve species, and within-species, selection so that the long-term outcome of mixtures is more predictable.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Kaiser Permanente Southern California began offering a 4-week supplemental benefit of home-delivered meals to Medicare Advantage members after discharge from a hospitalization for heart failure and ...other medical conditions in 2021. The purpose of this study is to explore the associations between socioeconomic disadvantage and food insecurity with patient uptake of and satisfaction with the meals.
Data for this cross-sectional study were drawn from survey and electronic medical record data for members referred for the meals benefit (n = 6169) and linked to a hospitalization encounter (n = 2254) between January and December 2021. Uptake was assessed using vendor records; measures of socioeconomic status included the neighborhood deprivation index (NDI) and prior receipt of medical financial assistance (MFA) from the health system. Patients were invited to complete an email or phone survey about their satisfaction with the meals and food insecurity. Multivariable log-binomial regression models were used to examine the association between socioeconomic disadvantage and food insecurity with meals uptake and satisfaction.
Sixty-two percent of patients referred for the benefit accepted the meals (mean age: 79 ± 9, 59% people of color). While there was no significant relationship between NDI and meals uptake (RR: 0.99, 95% CI: 0.92-1.07, p = 0.77), patients who received prior MFA were more likely to accept the meals (RR: 1.09, 95% CI: 1.02-1.16, p < 0.01). Sixty-nine percent of patients who completed the survey (23% response rate) reported that meals were very or extremely helpful. Patients with food insecurity (29% of survey respondents) were more likely to report that the meals were helpful for their recovery compared to food secure patients (RR: 1.21, 95% CI: 1.09-1.35, p < 0.01).
The home-delivered meals appeared to be particularly utilized by and helpful to patients with greater financial strain and/or food insecurity, suggesting that supplemental benefits could be more targeted toward addressing unmet needs of vulnerable adults.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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