ABSTRACT
BACKGROUND: There is widespread interest in the general factor of psychopathology or 'p factor', which has been proposed to reflect vulnerability to psychopathology. We examined to what extent this 'vulnerability' is associated with dysregulations in affect and behavior that occur in daily life. As such we hoped to provide an account of how this vulnerability may be maintained. METHODS: We used data from the Tracking Adolescents' Individual Lives Survey (TRAILS; N = 2,772) collected at ages 11, 14, 16, 19, and 22 years to fit a bifactor model with a general psychopathology factor, alongside internalizing, externalizing (EXT), attention-deficit/hyperactivity, and autism spectrum problem domains. Following the fifth TRAILS assessment, a subsample of participants (n = 133, age = 22.6, 43% women) with heightened risk for psychopathology completed a 6-month daily diary protocol with one assessment each day. Using a dynamic structural equation approach, we examined to what extent mean intensity, variability, inertia, and within-day co-occurrence of EXT, anxious-tense, and depressed-withdrawn affects and behaviors were associated with general factor scores. RESULTS: Unexpectedly, higher general factor scores were not associated with higher mean intensity of any of the three types of daily negative affects and behaviors, but were associated with higher variability and less carryover (inertia) EXT affects and behaviors. CONCLUSIONS: We showed that individual differences in general factor scores do not manifest as differences in average levels of daily affects and behaviors, but instead were related to a type of EXT reactivity to the environment. Future research is necessary to investigate whether reactive irritable moods may be involved in or signal vulnerability sustained psychopathology.
Subject(s)
Mental Disorders , Adolescent , Child , Female , Humans , Male , Young Adult , Mental Disorders/epidemiologyABSTRACT
BACKGROUND: The general factor of psychopathology, often denoted as p, captures the common variance among a broad range of psychiatric symptoms. Specific factors are co-modeled based on subsets of closely related symptoms. This paper investigated the extent to which wide-ranging genetic, personal, and environmental etiologically relevant variables are associated with p and specific psychopathology factors. METHODS: Using data from four waves (ages 11-19) of TRAILS, we modeled a bifactor model of p and four specific factors [internalizing, externalizing, ADHD, Autism Spectrum Disorder (ASD)]. Next, we examined the associations of 19 etiologically relevant variables with these psychology factors using path models that organized the variables according to the distal-to-proximal risk principle. RESULTS: Collectively, the etiologically relevant factors, including temperament traits, accounted for 55% of p's variance, 46% in ADHD, 35% in externalizing, 19% in internalizing, and 7% in ASD. The low 7% is due to insufficient unique variance in ASD indicators that load more strongly on p. Excluding temperament, variables accounted for 29% variance in p, 9% ADHD, 14% EXT, 7% INT, and 4% ASD. Most etiologically relevant factors were generic, predicting p. In addition, we identified effects on specific factors in addition to effects on p (e.g., parental SES, executive functioning); only effects on specific factors (e.g., parental rejection); opposite effects on different factors [e.g., diurnal cortisol (high INT but low EXT, p); developmental delay (high ASD and p but low EXT)]. Frustration, family functioning, parental psychopathology, executive functioning, and fearfulness had strong effects on p. CONCLUSIONS: (1) Strong generic effects on p suggest that etiologically relevant factors and psychopathology tend to cluster in persons. (2) While many factors predict p, additional as well as opposite effects on specific factors indicate the relevance of specific psychopathology factors in understanding mental disorder. (3) High frustration, neurodevelopmental problems, and a disadvantaged family environment primarily characterize p.
ABSTRACT
Energy production via the mitochondrial electron transport chain (ETC) and mitophagy are two important processes affected in Parkinson's disease (PD). Interestingly, PINK1, mutations of which cause early-onset PD, plays a key role in both processes, suggesting that these two mechanisms are connected. However, the converging link of both pathways currently remains enigmatic. Recent findings demonstrated that lipid aggregation, along with defective mitochondria, is present in postmortem brains of PD patients. In addition, an increasing body of evidence shows that sphingolipids, including ceramide, are altered in PD, supporting the importance of lipids in the pathophysiology of PD. Here, we identified ceramide to play a crucial role in PINK1-related PD that was previously linked almost exclusively to mitochondrial dysfunction. We found ceramide to accumulate in mitochondria and to negatively affect mitochondrial function, most notably the ETC. Lowering ceramide levels improved mitochondrial phenotypes in pink1-mutant flies and PINK1-deficient patient-derived fibroblasts, showing that the effects of ceramide are evolutionarily conserved. In addition, ceramide accumulation provoked ceramide-induced mitophagy upon PINK1 deficiency. As a result of the ceramide accumulation, ß-oxidation in PINK1 mutants was decreased, which was rescued by lowering ceramide levels. Furthermore, stimulation of ß-oxidation was sufficient to rescue PINK1-deficient phenotypes. In conclusion, we discovered a cellular mechanism resulting from PD-causing loss of PINK1 and found a protective role of ß-oxidation in ETC dysfunction, thus linking lipids and mitochondria in the pathophysiology of PINK1-related PD. Furthermore, our data nominate ß-oxidation and ceramide as therapeutic targets for PD.
Subject(s)
Ceramides/metabolism , Mitophagy/physiology , Parkinson Disease/physiopathology , Protein Kinases/deficiency , Animals , Autophagy , Drosophila Proteins/deficiency , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Fibroblasts/metabolism , Fibroblasts/pathology , Humans , Lipid Metabolism , Mice , Mice, Knockout , Mitophagy/genetics , Oxidation-Reduction , Oxidoreductases/antagonists & inhibitors , Oxidoreductases/genetics , Parkinson Disease/genetics , Parkinson Disease/pathology , Protein Kinases/genetics , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/deficiency , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolismABSTRACT
De novo variants represent a significant cause of neurodevelopmental delay and intellectual disability. A genetic basis can be identified in only half of individuals who have neurodevelopmental disorders (NDDs); this indicates that additional causes need to be elucidated. We compared the frequency of de novo variants in patient-parent trios with (n = 2,030) versus without (n = 2,755) NDDs. We identified de novo variants in TAOK1 (thousand and one [TAO] amino acid kinase 1), which encodes the serine/threonine-protein kinase TAO1, in three individuals with NDDs but not in persons who did not have NDDs. Through further screening and the use of GeneMatcher, five additional individuals with NDDs were found to have de novo variants. All eight variants were absent from gnomAD (Genome Aggregation Database). The variant carriers shared a non-specific phenotype of developmental delay, and six individuals had additional muscular hypotonia. We established a fibroblast line of one mutation carrier, and we demonstrated that reduced mRNA levels of TAOK1 could be increased upon cycloheximide treatment. These results indicate nonsense-mediated mRNA decay. Further, there was neither detectable phosphorylated TAO1 kinase nor phosphorylated tau in these cells, and mitochondrial morphology was altered. Knockdown of the ortholog gene Tao1 (Tao, CG14217) in Drosophila resulted in delayed early development. The majority of the Tao1-knockdown flies did not survive beyond the third instar larval stage. When compared to control flies, Tao1 knockdown flies revealed changed morphology of the ventral nerve cord and the neuromuscular junctions as well as a decreased number of endings (boutons). Furthermore, mitochondria in mutant flies showed altered distribution and decreased size in axons of motor neurons. Thus, we provide compelling evidence that de novo variants in TAOK1 cause NDDs.
Subject(s)
Drosophila melanogaster/growth & development , Exome/genetics , Mutation , Neurodevelopmental Disorders/etiology , Protein Serine-Threonine Kinases/genetics , Animals , Child , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Female , Heterozygote , Humans , Male , Neurodevelopmental Disorders/pathology , Phenotype , Exome SequencingABSTRACT
To advance understanding of the heterogeneity in the course of ADHD, joint symptom trajectories of inattention and hyperactivity-impulsivity from childhood to young adulthood were modelled and associated with genetic, demographic, and clinical characteristics. Data were obtained from the NeuroIMAGE cohort which includes 485 individuals with ADHD, their 665 siblings, and 399 typically developing children. Trajectories were based on scores of the Conners Parent Rating Scale Revised and estimated over seven homogeneous age bins (from 5 to 28 years) using parallel process latent class growth analysis on data collected across 2-4 time points. Multilevel multinomial logistic regression was used to identify characteristics that differentiated between the derived classes. A seven-class solution revealed "severe combined stable" (4.8%), "severe combined decreasing" (13%), "severe inattentive stable" (4.8%), "moderate combined increasing" (7.5%), "moderate combined decreasing" (12.7%), "stable mild" (12.9%), and "stable low" (44.3%) classes. Polygenic risk for depression, ADHD diagnosis, ADHD medication use, IQ, comorbid symptom levels (foremost oppositional behaviour), and functional impairment levels differentiated classes with similar ADHD symptom levels in childhood but a diverging course thereafter. The course of ADHD is highly heterogeneous, with stable, decreasing, and increasing trajectories. Overall, severe symptom levels in childhood are associated with elevated-to-severe symptom levels in adolescence and young adulthood, despite substantial symptom reductions. Beyond symptom severity in childhood, genetic, demographic, and clinical characteristics distinguish the heterogeneous course.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Adolescent , Adult , Attention Deficit Disorder with Hyperactivity/epidemiology , Child , Child, Preschool , Cohort Studies , Comorbidity , Humans , Impulsive Behavior , Young AdultABSTRACT
Treatment planning of gastrointestinal stromal tumors (GISTs) includes distinguishing GISTs from other intra-abdominal tumors and GISTs' molecular analysis. The aim of this study was to evaluate radiomics for distinguishing GISTs from other intra-abdominal tumors, and in GISTs, predict the c-KIT, PDGFRA, BRAF mutational status, and mitotic index (MI). Patients diagnosed at the Erasmus MC between 2004 and 2017, with GIST or non-GIST intra-abdominal tumors and a contrast-enhanced venous-phase CT, were retrospectively included. Tumors were segmented, from which 564 image features were extracted. Prediction models were constructed using a combination of machine learning approaches. The evaluation was performed in a 100 × random-split cross-validation. Model performance was compared to that of three radiologists. One hundred twenty-five GISTs and 122 non-GISTs were included. The GIST vs. non-GIST radiomics model had a mean area under the curve (AUC) of 0.77. Three radiologists had an AUC of 0.69, 0.76, and 0.84, respectively. The radiomics model had an AUC of 0.52 for c-KIT, 0.56 for c-KIT exon 11, and 0.52 for the MI. The numbers of PDGFRA, BRAF, and other c-KIT mutations were too low for analysis. Our radiomics model was able to distinguish GISTs from non-GISTs with a performance similar to three radiologists, but less observer dependent. Therefore, it may aid in the early diagnosis of GIST, facilitating rapid referral to specialized treatment centers. As the model was not able to predict any genetic or molecular features, it cannot aid in treatment planning yet.
Subject(s)
Abdominal Neoplasms , Gastrointestinal Stromal Tumors , Diagnosis, Differential , Gastrointestinal Stromal Tumors/diagnostic imaging , Gastrointestinal Stromal Tumors/genetics , Gastrointestinal Stromal Tumors/pathology , Humans , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins c-kit/genetics , Retrospective Studies , Tomography, X-Ray ComputedABSTRACT
Beta-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA) caused by loss-of-function variants in WDR45. The underlying mechanism of iron accumulation in WDR45 deficiency remains elusive. We established a primary skin fibroblast culture of a new BPAN patient with a missense variant p.(Asn61Lys) in WDR45 (NM_007075.3: c.183C>A). The female patient has generalized dystonia, anarthria, parkinsonism, spasticity, stereotypies, and a distinctive cranial MRI with generalized brain atrophy, predominantly of the cerebellum. For the functional characterization of this variant and to provide a molecular link of WDR45 and iron accumulation, we looked for disease- and variant-related changes in the patient's fibroblasts by qPCR, immunoblotting and immunofluorescence comparing to three controls and a previously reported WDR45 patient. We demonstrated molecular changes in mutant cells comprising an impaired mitochondrial network, decreased levels of lysosomal proteins and enzymes, and altered autophagy, confirming the pathogenicity of the variant. Compared to increased levels of the ferritinophagy marker Nuclear Coactivator 4 (NCOA4) in control cells upon iron treatment, patients' cells revealed unchanged NCOA4 protein levels, indicating disturbed ferritinophagy. Additionally, we observed abnormal protein levels of markers of the iron-dependent cell death ferroptosis in patients' cells. Altogether, our data suggests that WDR45 deficiency affects ferritinophagy and ferroptosis, consequentially disturbing iron recycling.
Subject(s)
Carrier Proteins , Ferroptosis , Neurodegenerative Diseases , Autophagy/genetics , Brain/metabolism , Carrier Proteins/genetics , Carrier Proteins/metabolism , Female , Ferroptosis/genetics , Humans , Iron/metabolism , Magnetic Resonance Imaging , Neurodegenerative Diseases/geneticsABSTRACT
The prevalence of intellectual disability is around 3%; however, the etiology of the disease remains unclear in most cases. We identified a series of patients with X-linked intellectual disability presenting mutations in the Rad6a (Ube2a) gene, which encodes for an E2 ubiquitin-conjugating enzyme. Drosophila deficient for dRad6 display defective synaptic function as a consequence of mitochondrial failure. Similarly, mouse mRad6a (Ube2a) knockout and patient-derived hRad6a (Ube2a) mutant cells show defective mitochondria. Using in vitro and in vivo ubiquitination assays, we show that RAD6A acts as an E2 ubiquitin-conjugating enzyme that, in combination with an E3 ubiquitin ligase such as Parkin, ubiquitinates mitochondrial proteins to facilitate the clearance of dysfunctional mitochondria in cells. Hence, we identify RAD6A as a regulator of Parkin-dependent mitophagy and establish a critical role for RAD6A in maintaining neuronal function.
Subject(s)
Mental Retardation, X-Linked/genetics , Mitophagy , Ubiquitin-Conjugating Enzymes/genetics , Ubiquitin-Protein Ligases/metabolism , Adolescent , Adult , Animals , Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology , Case-Control Studies , Cell Line , Child , Drosophila , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Exome , Genetic Association Studies , Humans , Kinetics , Male , Membrane Potential, Mitochondrial , Mice , Mice, Knockout , Mitochondria, Muscle/drug effects , Mitochondria, Muscle/physiology , Mutation, Missense , Neuromuscular Junction/metabolism , Pedigree , Sequence Analysis, DNA , Ubiquitin-Conjugating Enzymes/metabolism , Ubiquitination , Uncoupling Agents/pharmacologyABSTRACT
Neurodegenerative diseases are incurable diseases of the nervous system that lead to a progressive loss of brain areas and neuronal subtypes, which is associated with an increase in symptoms that can be linked to the affected brain areas. The key findings that appear in many neurodegenerative diseases are deposits of proteins and the damage of mitochondria, which mainly affect energy production and mitophagy. Several causative gene mutations have been identified in various neurodegenerative diseases; however, a large proportion are considered sporadic. In the last decade, studies linking lipids, and in particular sphingolipids, to neurodegenerative diseases have shown the importance of these sphingolipids in the underlying pathogenesis. Sphingolipids are bioactive lipids consisting of a sphingoid base linked to a fatty acid and a hydrophilic head group. They are involved in various cellular processes, such as cell growth, apoptosis, and autophagy, and are an essential component of the brain. In this review, we will cover key findings that demonstrate the relevance of sphingolipids in neurodegenerative diseases and will focus on neurodegeneration with brain iron accumulation and Parkinson's disease.
Subject(s)
Ceramides/metabolism , Mitochondria/metabolism , Neurodegenerative Diseases/metabolism , Sphingolipids/metabolism , Animals , Humans , Mitochondria/pathology , Mitophagy , Neurodegenerative Diseases/pathologyABSTRACT
BACKGROUND: Treatment options for patients with metastatic soft tissue sarcoma (STS) have increased in the last decade. We aimed to examine whether this is associated with improved overall survival (OS) in patients with STS with synchronous metastases. PATIENTS AND METHODS: Patients diagnosed with STS and synchronous metastases from 1989 to 2014 were queried from The Netherlands Cancer Registry. Trends in OS were assessed by the Kaplan-Meier method and log-rank test in time intervals of 5 years, for the whole study population and in subgroups for liposarcomas, leiomyosarcoma, and other STS subtypes. A multivariable Cox regression analysis was performed to identify characteristics prognostic for OS. RESULTS: Median OS of the 1,393 identified patients did not improve significantly over the years from 5.8 months in 1989-1994 to 8.1 months in 2010-2014, but there was an evident trend. Median OS was prolonged in the subgroups of liposarcomas (3.6 to 9.3 months), leiomyosarcomas (11.3 to 14.6 months), and other STS subtypes (5.7 to 6.3 months), although there were no significant improvements in OS over the years. Primary tumor site in one of the extremities and surgery in an academic center had a favorable effect on OS, whereas significant negative predictors were no treatment, elderly age, STS subtype other than liposarcoma or leiomyosarcoma, high or unknown grade, and nodal involvement. CONCLUSION: Although overall survival of patients with STS with synchronous metastases in this nationwide and "real-life" population has improved over the years, the improvement was not statistically significant, despite new treatment options. IMPLICATIONS FOR PRACTICE: Treatment of patients with metastatic soft tissue sarcoma (STS) has changed in the past years, with new drugs such as trabectedin (2007) and pazopanib (2012) becoming available. By using data from the nationwide Netherlands Cancer Registry, the impact of these changes in treatment policies on survival is analyzed in a "real-life" population of patients with STS with synchronous metastases, rather than in a strictly selected trial population. Unfortunately, overall survival improved only minimally and not significantly for these patients diagnosed from 1989 to 2014. Hopefully, the advent of novel treatment options, such as eribulin and olaratumab, will further improve the outcome of this patient group.
Subject(s)
Sarcoma/complications , Sarcoma/mortality , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Prognosis , Survival Analysis , Young AdultABSTRACT
Background: There is an unmet need for markers predicting the outcome of patients with advanced soft tissue sarcoma (STS) treated with pazopanib. Since toxicity might be related to the anti-tumor activity of the drug, the aim of this study was to determine whether pazopanib-induced proteinuria, hypothyroidism and cardiotoxicity grade 3-4 were associated with outcome. Methods: The combined results of the EORTC 62043 and 62072 trials were retrospectively assessed and used in a landmark analysis to evaluate the effect of the toxicities on progression-free survival (PFS) and overall survival (OS), using the Kaplan-Meier method and Cox regression models. Results: Of the 333 eligible patients, 259 patients were included in the analyses, for which a landmark time point of 60 days after randomization/registration was selected. Proteinuria occurred in 25.1%, hypothyroidism in 22.0% and cardiotoxicity grade 3-4 in 5.8% of the patients (any grade in 41.7%). There was no effect of the occurrence of proteinuria (6-months PFS 35.4% for patients with vs. 38.3% for patients without proteinuria, HR 1.01, p = .953), hypothyroidism (41.2% vs. 36.5%, HR 0.82, p = .210) or cardiotoxicity grade 3-4 (26.7% vs. 38.2%, HR 0.97, p = .897) on PFS. Nor was there an effect of proteinuria (6-months OS 63.2% for patients with vs. 74.4% for patients without proteinuria, HR 1.22, p = .196), hypothyroidism (76.2% vs. 70.5%, HR 0.75, p = .093) or cardiotoxicity grade 3-4 (80.0% vs. 77.2%, HR 0.93, p = .801) on OS. Conclusion: There was no association between the occurrence of pazopanib-induced proteinuria, hypothyroidism and cardiotoxicity and outcome. Therefore, these toxicities cannot be used as predictors for pazopanib activity in patients with advanced STS.
Subject(s)
Angiogenesis Inhibitors/adverse effects , Cardiotoxicity/mortality , Hypothyroidism/mortality , Proteinuria/mortality , Pyrimidines/adverse effects , Sarcoma/drug therapy , Sulfonamides/adverse effects , Cardiotoxicity/etiology , Cardiotoxicity/pathology , Female , Follow-Up Studies , Humans , Hypothyroidism/chemically induced , Hypothyroidism/pathology , Indazoles , Male , Middle Aged , Prognosis , Proteinuria/chemically induced , Proteinuria/pathology , Retrospective Studies , Sarcoma/pathology , Survival RateABSTRACT
The PTEN-induced kinase 1 (PINK1) is a mitochondrial kinase, and pink1 mutations cause early onset Parkinson's disease (PD) in humans. Loss of pink1 in Drosophila leads to defects in mitochondrial function, and genetic data suggest that another PD-related gene product, Parkin, acts with pink1 to regulate the clearance of dysfunctional mitochondria (mitophagy). Consequently, pink1 mutants show an accumulation of morphologically abnormal mitochondria, but it is unclear if other factors are involved in pink1 function in vivo and contribute to the mitochondrial morphological defects seen in specific cell types in pink1 mutants. To explore the molecular mechanisms of pink1 function, we performed a genetic modifier screen in Drosophila and identified aconitase (acon) as a dominant suppressor of pink1. Acon localizes to mitochondria and harbors a labile iron-sulfur [4Fe-4S] cluster that can scavenge superoxide to release hydrogen peroxide and iron that combine to produce hydroxyl radicals. Using Acon enzymatic mutants, and expression of mitoferritin that scavenges free iron, we show that [4Fe-4S] cluster inactivation, as a result of increased superoxide in pink1 mutants, results in oxidative stress and mitochondrial swelling. We show that [4Fe-4S] inactivation acts downstream of pink1 in a pathway that affects mitochondrial morphology, but acts independently of parkin. Thus our data indicate that superoxide-dependent [4Fe-4S] inactivation defines a potential pathogenic cascade that acts independent of mitophagy and links iron toxicity to mitochondrial failure in a PD-relevant model.
Subject(s)
Aconitate Hydratase , Drosophila , Animals , Drosophila/genetics , Drosophila Proteins/genetics , Humans , Iron/metabolism , Mitochondria/genetics , Parkinson Disease/geneticsABSTRACT
It is estimated that the human mitochondrial proteome consists of 1000-1500 distinct proteins. The majority of these support the various biochemical pathways that are active in these organelles. Individuals with an oxidative phosphorylation disorder of unknown cause provide a unique opportunity to identify novel genes implicated in mitochondrial biology. We identified a homozygous deletion of CEP89 in a patient with isolated complex IV deficiency, intellectual disability and multisystemic problems. CEP89 is a ubiquitously expressed and highly conserved gene of unknown function. Immunocytochemistry and cellular fractionation experiments showed that CEP89 is present both in the cytosol and in the mitochondrial intermembrane space. Furthermore, we ascertained in vitro that downregulation of CEP89 resulted in a severe decrease in complex IV in-gel activity and altered mobility, suggesting that the complex is aberrantly formed. Two-dimensional BN-SDS gel analysis revealed that CEP89 associates with a high-molecular weight complex. Together, these data confirm a role for CEP89 in mitochondrial metabolism. In addition, we modeled CEP89 loss of function in Drosophila. Ubiquitous knockdown of fly Cep89 decreased complex IV activity and resulted in complete lethality. Furthermore, Cep89 is required for mitochondrial integrity, membrane depolarization and synaptic transmission of photoreceptor neurons, and for (sub)synaptic organization of the larval neuromuscular junction. Finally, we tested neuronal Cep89 knockdown flies in the light-off jump reflex habituation assay, which revealed its role in learning. We conclude that CEP89 proteins play an important role in mitochondrial metabolism, especially complex IV activity, and are required for neuronal and cognitive function across evolution.
Subject(s)
Cell Cycle Proteins/metabolism , Drosophila Proteins/metabolism , Drosophila/metabolism , Mitochondria/metabolism , Neurons/metabolism , Animals , Cell Cycle Proteins/genetics , Child , Chromosomes, Human, Pair 19 , Cytochrome-c Oxidase Deficiency/genetics , Cytochrome-c Oxidase Deficiency/metabolism , Cytosol , Disease Models, Animal , Drosophila/genetics , Drosophila Proteins/genetics , Female , Gene Deletion , Gene Expression , Gene Knockdown Techniques , Homozygote , Humans , Learning , Microtubule-Associated Proteins , Mitochondria/genetics , Mutation , Organ Specificity/genetics , Polymorphism, Single Nucleotide , Protein Transport , Synapses/genetics , Synapses/metabolismABSTRACT
Parkinson's disease (PD) is a neurodegenerative motor disorder characterized by the loss of dopaminergic neurons. This loss of dopaminergic neurons is the pathological hallmark of the disease that results in the characteristic motor syndrome. Restoration of dopamine levels is the basis of current therapy; however, this does not tackle the cause of the disease. While the aetiology of PD remains mostly elusive, mitochondrial dysfunction has been linked to (at least) part of the PD cases. In this review we discuss recent findings in Drosophila melanogaster showing that stimulation of the electron transport chain is beneficial for PD fly models showing Complex I defects and discuss the possible clinical applications of these findings.
Subject(s)
Dopamine/metabolism , Drosophila Proteins/metabolism , Electron Transport Complex I/metabolism , Mitochondria/metabolism , Parkinson Disease/therapy , Protein Serine-Threonine Kinases/metabolism , Animals , Disease Models, Animal , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/pathology , Drosophila Proteins/genetics , Drosophila melanogaster , Humans , Mitochondria/pathology , Parkinson Disease/metabolism , Parkinson Disease/pathology , Protein Serine-Threonine Kinases/genetics , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
Pink1 is a mitochondrial kinase involved in Parkinson's disease, and loss of Pink1 function affects mitochondrial morphology via a pathway involving Parkin and components of the mitochondrial remodeling machinery. Pink1 loss also affects the enzymatic activity of isolated Complex I of the electron transport chain (ETC); however, the primary defect in pink1 mutants is unclear. We tested the hypothesis that ETC deficiency is upstream of other pink1-associated phenotypes. We expressed Saccaromyces cerevisiae Ndi1p, an enzyme that bypasses ETC Complex I, or sea squirt Ciona intestinalis AOX, an enzyme that bypasses ETC Complex III and IV, in pink1 mutant Drosophila and find that expression of Ndi1p, but not of AOX, rescues pink1-associated defects. Likewise, loss of function of subunits that encode for Complex I-associated proteins displays many of the pink1-associated phenotypes, and these defects are rescued by Ndi1p expression. Conversely, expression of Ndi1p fails to rescue any of the parkin mutant phenotypes. Additionally, unlike pink1 mutants, fly parkin mutants do not show reduced enzymatic activity of Complex I, indicating that Ndi1p acts downstream or parallel to Pink1, but upstream or independent of Parkin. Furthermore, while increasing mitochondrial fission or decreasing mitochondrial fusion rescues mitochondrial morphological defects in pink1 mutants, these manipulations fail to significantly rescue the reduced enzymatic activity of Complex I, indicating that functional defects observed at the level of Complex I enzymatic activity in pink1 mutant mitochondria do not arise from morphological defects. Our data indicate a central role for Complex I dysfunction in pink1-associated defects, and our genetic analyses with heterologous ETC enzymes suggest that Ndi1p-dependent NADH dehydrogenase activity largely acts downstream of, or in parallel to, Pink1 but upstream of Parkin and mitochondrial remodeling.
Subject(s)
Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Electron Transport Complex I/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Animals, Genetically Modified/genetics , Animals, Genetically Modified/metabolism , Ciona intestinalis/genetics , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , Electron Transport Complex I/genetics , Electron Transport Complex III/genetics , Electron Transport Complex III/metabolism , Electron Transport Complex IV/genetics , Electron Transport Complex IV/metabolism , GTP-Binding Proteins/genetics , GTP-Binding Proteins/metabolism , Gene Expression Regulation , Humans , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mitochondria/genetics , Mitochondria/metabolism , Mitochondrial Proteins/metabolism , Mutation , Oxidoreductases/metabolism , Parkinson Disease/genetics , Plant Proteins/metabolism , Saccharomyces cerevisiae/genetics , Ubiquitin-Protein Ligases/geneticsSubject(s)
Parkinson Disease , REM Sleep Behavior Disorder , Sleep Wake Disorders , Humans , Lipids , NeuronsABSTRACT
Sphingolipids, including the basic ceramide, are a subset of bioactive lipids that consist of many different species. Sphingolipids are indispensable for proper neuronal function, and an increasing number of studies have emerged on the complexity and importance of these lipids in (almost) all biological processes. These include regulation of mitochondrial function, autophagy, and endosomal trafficking, which are affected in Parkinson's disease (PD). PD is the second most common neurodegenerative disorder and is characterized by the loss of dopaminergic neurons. Currently, PD cannot be cured due to the lack of knowledge of the exact pathogenesis. Nonetheless, important advances have identified molecular changes in mitochondrial function, autophagy, and endosomal function. Furthermore, recent studies have identified ceramide alterations in patients suffering from PD, and in PD models, suggesting a critical interaction between sphingolipids and related cellular processes in PD. For instance, autosomal recessive forms of PD cause mitochondrial dysfunction, including energy production or mitochondrial clearance, that is directly influenced by manipulating sphingolipids. Additionally, endo-lysosomal recycling is affected by genes that cause autosomal dominant forms of the disease, such as VPS35 and SNCA. Furthermore, endo-lysosomal recycling is crucial for transporting sphingolipids to different cellular compartments where they will execute their functions. This review will discuss mitochondrial dysfunction, defects in autophagy, and abnormal endosomal activity in PD and the role sphingolipids play in these vital molecular processes.
Subject(s)
Ceramides , Parkinson Disease , Sphingolipids , Humans , Ceramides/metabolism , Dopaminergic Neurons/metabolism , Mitochondria/genetics , Mitochondria/pathology , Parkinson Disease/metabolism , Sphingolipids/metabolismABSTRACT
LAY ABSTRACT: There is an ongoing debate as to whether autism spectrum disorder (ASD) is expressed differently in women than men. Studies on sex differences in autistic symptoms and symptoms of other psychiatric problems present in individuals with autism generally do not include a general population comparison group, making it unclear whether differences are specific to autism or merely reflecting development in the general population. In this study, we compared sex differences in the course of autistic and at the same time present symptoms of other psychiatric problems in adolescents with milder forms of ASD to those in a group of the general population with an equal intelligence quotient (IQ) and socioeconomic status. Data of five assessment moments from ages 11 to 22 years were analyzed using a statistic procedure that allowed us to determine which factors affect the course of symptoms over time. We found that in adolescence, sex differences in the course of psychopathological symptoms specific for autism are confined to the repetitive stereotyped domains. Males had higher scores on the sensory/stereotypic and resistance to change domains, the latter difference disappeared during the course of adolescence due to an increase of these problems in autistic females. Other sex differences, among which an increase over time in mood and anxiety problems in females was the most outstanding, were also observed in females without autism. These sex-specific differences have relevance in the clinical care of autistic men and women, although they are subtle compared to differences between individuals with and without autism.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Humans , Female , Male , Adolescent , Autistic Disorder/epidemiology , Autism Spectrum Disorder/psychology , Sex Characteristics , Longitudinal Studies , Stereotyped BehaviorABSTRACT
Despite being a major component of Lewy bodies and Lewy neurites, pathogenic variants in the gene encoding alpha-Synuclein (α-Syn) are rare. To date, only four missense variants in the SNCA gene, encoding α-Syn have unequivocally been shown to be disease-causing. We here describe a Parkinson´s disease patient with early cognitive decline carrying an as yet not fully characterized variant in SNCA (NM_001146055: c.44T > C, p.V15A). We used different cellular models, including stably transfected neuroblastoma (SH-SY5Y) cell cultures, induced pluripotent stem cell (iPSC)-derived neuronal cultures, and generated a Drosophila model to elucidate the impact of the p.V15A variant on α-Syn function and aggregation properties compared to other known pathogenic variants. We demonstrate that p.V15A increased the aggregation potential of α-Syn and the levels of apoptotic markers, and impaired the mitochondrial network. Moreover, p.V15A affects the flying ability and survival of mutant flies. Thus, we provide supporting evidence for the pathogenicity of the p.V15A variant, suggesting its inclusion in genetic testing approaches.
ABSTRACT
Knowledge on psychiatric comorbidity in adult ADHD is essential for prevention, detection, and treatment of these conditions. This review (1) focuses on large studies (n > 10,000; surveys, claims data, population registries) to identify (a) overall, (b) sex- and (c) age-specific patterns of comorbidity of anxiety disorders (ADs), major depressive disorder (MDD), bipolar disorder (BD) and substance use disorders (SUDs) in adults with ADHD relative to adults without ADHD; and (2) describes methodological challenges relating to establishing comorbidity in ADHD in adults as well as priorities for future research. Meta-analyses (ADHD: n = 550,748; no ADHD n = 14,546,814) yielded pooled odds ratios of 5.0(CI:3.29-7.46) for ADs, 4.5(CI:2.44-8.34) for MDD, 8.7(CI:5.47-13.89) for BD and 4.6(CI:2.72-7.80) for SUDs, indicating strong differences in adults with compared to adults without ADHD. Moderation by sex was not found: high comorbidity held for both men and women with sex-specific patterns as in the general population: higher prevalences of ADs, MDD and BD in women and a higher prevalence of SUDs in men. Insufficient data on different phases of the adult lifespan prevented conclusions on developmental changes in comorbidity. We discuss methodological challenges, knowledge gaps, and future research priorities.