References of "Neurobiology of disease"
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See detailIntegrative analysis of blood metabolomics and PET brain neuroimaging data for Parkinson's disease
Glaab, Enrico UL; Trezzi, Jean-Pierre UL; Greuel, Andrea et al

in Neurobiology of Disease (2019), 124(1), 555-562

The diagnosis of Parkinson's disease (PD) often remains a clinical challenge. Molecular neuroimaging can facilitate the diagnostic process. The diagnostic potential of metabolomic signatures has recently ... [more ▼]

The diagnosis of Parkinson's disease (PD) often remains a clinical challenge. Molecular neuroimaging can facilitate the diagnostic process. The diagnostic potential of metabolomic signatures has recently been recognized. Methods: We investigated whether the joint data analysis of blood metabolomics and PET imaging by machine learning provides enhanced diagnostic discrimination and gives further pathophysiological insights. Blood plasma samples were collected from 60 PD patients and 15 age- and gender-matched healthy controls. We determined metabolomic profiles by gas chromatography coupled to mass spectrometry (GC-MS). In the same cohort and at the same time we performed FDOPA PET in 44 patients and 14 controls and FDG PET in 51 patients and 16 controls. 18 PD patients were available for a follow-up exam after one year. Both data sets were analysed by two machine learning approaches, applying either linear support vector machines or random forests within a leave-one-out cross-validation and computing receiver operating characteristic (ROC) curves. Results: In the metabolomics data, the baseline comparison between cases and controls as well as the followup assessment of patients pointed to metabolite changes associated with oxidative stress and inflammation. For the FDOPA and FDG PET data, the diagnostic predictive performance (DPP) in the ROC analyses was highest when combining imaging features with metabolomics data (ROC AUC for best FDOPA + metabolomics model: 0.98; AUC for best FDG + metabolomics model: 0.91). DPP was lower when using only PET attributes or only metabolomics signatures. Conclusion: Integrating blood metabolomics data combined with PET data considerably enhances the diagnostic discrimination power. Metabolomic signatures also indicate interesting disease-inherent changes in cellular processes, including oxidative stress response and inflammation. [less ▲]

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See detailAlpha-synuclein deregulates the expression of COL4A2 and impairs ER-Golgi function
Paiva, Isabel; Jain, Garav; Lázaro, Diana F et al

in Neurobiology of Disease (2018)

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See detailA systems level analysis of epileptogenesis-associated proteome alterations.
Keck, Michael; Androsova, Ganna UL; Gualtieri, Fabio et al

in Neurobiology of disease (2017), 105

Despite intense research efforts, the knowledge about the mechanisms of epileptogenesis and epilepsy is still considered incomplete and limited. However, an in-depth understanding of molecular ... [more ▼]

Despite intense research efforts, the knowledge about the mechanisms of epileptogenesis and epilepsy is still considered incomplete and limited. However, an in-depth understanding of molecular pathophysiological processes is crucial for the rational selection of innovative biomarkers and target candidates. Here, we subjected proteomic data from different phases of a chronic rat epileptogenesis model to a comprehensive systems level analysis. Weighted Gene Co-expression Network analysis identified several modules of interconnected protein groups reflecting distinct molecular aspects of epileptogenesis in the hippocampus and the parahippocampal cortex. Characterization of these modules did not only further validate the data but also revealed regulation of molecular processes not described previously in the context of epilepsy development. The data sets also provide valuable information about temporal patterns, which should be taken into account for development of preventive strategies in particular when it comes to multi-targeting network pharmacology approaches. In addition, principal component analysis suggests candidate biomarkers, which might inform the design of novel molecular imaging approaches aiming to predict epileptogenesis during different phases or confirm epilepsy manifestation. Further studies are necessary to distinguish between molecular alterations, which correlate with epileptogenesis versus those reflecting a mere consequence of the status epilepticus. [less ▲]

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See detailLoss of DJ-1 impairs antioxidant response by altered glutamine and serine metabolism
Meiser, Johannes UL; Delcambre, Sylvie UL; Wegner, André UL et al

in Neurobiology of disease (2016), 89

The oncogene DJ-1 has been originally identified as a suppressor of PTEN. Further on, loss-of-function mutations have been described as a causative factor in Parkinson's disease (PD). DJ-1 has an ... [more ▼]

The oncogene DJ-1 has been originally identified as a suppressor of PTEN. Further on, loss-of-function mutations have been described as a causative factor in Parkinson's disease (PD). DJ-1 has an important function in cellular antioxidant responses, but its role in central metabolism of neurons is still elusive. We applied stable isotope assisted metabolic profiling to investigate the effect of a functional loss of DJ-1 and show that DJ-1 deficient neuronal cells exhibit decreased glutamine influx and reduced serine biosynthesis. By providing precursors for GSH synthesis, these two metabolic pathways are important contributors to cellular antioxidant response. Down-regulation of these pathways, as a result of loss of DJ-1 leads to an impaired antioxidant response. Furthermore, DJ-1 deficient mouse microglia showed a weak but constitutive pro-inflammatory activation. The combined effects of altered central metabolism and constitutive activation of glia cells raise the susceptibility of dopaminergic neurons towards degeneration in patients harboring mutated DJ-1. Our work reveals metabolic alterations leading to increased cellular instability and identifies potential new intervention points that can further be studied in the light of novel translational medicine approaches. [less ▲]

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See detailComparative pathway and network analysis of brain transcriptome changes during adult aging and in Parkinson's disease
Glaab, Enrico UL; Schneider, Reinhard UL

in Neurobiology of Disease (2015), 74

Aging is considered as one of the main factors promoting the risk for Parkinson's disease (PD) and common mechanisms of dopamine neuron degeneration in aging and PD have been proposed in recent years ... [more ▼]

Aging is considered as one of the main factors promoting the risk for Parkinson's disease (PD) and common mechanisms of dopamine neuron degeneration in aging and PD have been proposed in recent years. Here, we use a statistical meta-analysis of human brain transcriptomics data to investigate potential mechanistic relationships between adult brain aging and PD pathogenesis at the pathway and network level. The analyses identify statistically significant shared pathway and network alterations in aging and PD and an enrichment in PD-associated sequence variants from genome-wide association studies among the jointly deregulated genes. We find robust discriminative patterns for groups of functionally related genes with potential applications as combined risk biomarkers to detect aging- and PD-linked oxidative stress, e.g. a consistent over-expression of metallothioneins matching with findings in previous independent studies. Interestingly, analyzing the regulatory network and mouse knockout expression data for the transcription factor NR4A2, previously associated with rare mutations in PD and here found as the most significantly under-expressed gene in PD among the jointly altered genes, suggests that aging-related NR4A2 expression changes may increase PD risk by producing downstream effects similar to disease-linked mutations and to expression changes observed in sporadic PD. Overall, the analyses suggest mechanistic explanations for the age-dependence of PD risk, reveal significant and robust shared process alterations in aging and PD, and examine their potential for biomarker applications in pre-symptomatic risk assessment or early-stage diagnosis. [less ▲]

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See detailThe modulation of Amyotrophic Lateral Sclerosis risk by ataxin-2 intermediate polyglutamine expansions is a specific effect.
Gispert, Suzana; Kurz, Alexander; Waibel, Stefan et al

in Neurobiology of disease (2012), 45(1), 356-61

Full expansions of the polyglutamine domain (polyQ>/=34) within the polysome-associated protein ataxin-2 (ATXN2) are the cause of a multi-system neurodegenerative disorder, which usually presents as a ... [more ▼]

Full expansions of the polyglutamine domain (polyQ>/=34) within the polysome-associated protein ataxin-2 (ATXN2) are the cause of a multi-system neurodegenerative disorder, which usually presents as a Spino-Cerebellar Ataxia and is therefore known as SCA2, but may rarely manifest as Levodopa-responsive Parkinson syndrome or as motor neuron disease. Intermediate expansions (27</=polyQ</=33) were reported to modify the risk of Amyotrophic Lateral Sclerosis (ALS). We have now tested the reproducibility and the specificity of this observation. In 559 independent ALS patients from Central Europe, the association of ATXN2 expansions (30</=polyQ</=35) with ALS was highly significant. The study of 1490 patients with Parkinson's disease (PD) showed an enrichment of ATXN2 alleles 27/28 in a subgroup with familial cases, but the overall risk of sporadic PD was unchanged. No association was found between polyQ expansions in Ataxin-3 (ATXN3) and ALS risk. These data indicate a specific interaction between ATXN2 expansions and the causes of ALS, possibly through altered RNA-processing as a common pathogenic factor. [less ▲]

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See detailOlfactory neuron-specific expression of A30P alpha-synuclein exacerbates dopamine deficiency and hyperactivity in a novel conditional model of early Parkinson's disease stages.
Nuber, Silke; Petrasch-Parwez, Elisabeth; Arias-Carrion, Oscar et al

in Neurobiology of disease (2011), 44(2), 192-204

Mutations in the N-terminus of the gene encoding alpha-synuclein (alpha-syn) are linked to autosomal dominantly inherited Parkinson's disease (PD). The vast majority of PD patients develop ... [more ▼]

Mutations in the N-terminus of the gene encoding alpha-synuclein (alpha-syn) are linked to autosomal dominantly inherited Parkinson's disease (PD). The vast majority of PD patients develop neuropsychiatric symptoms preceding motor impairments. During this premotor stage, synucleinopathy is first detectable in the olfactory bulb (OB) and brain stem nuclei; however its impact on interconnected brain regions and related symptoms is still less far understood. Using a novel conditional transgenic mouse model, displaying region-specific expression of human mutant alpha-syn, we evaluated effect and reversibility of olfactory synucleinopathy. Our data showed that induction of mutant A30P alpha-syn expression increased transgenic deposition into somatodendritic compartment of dopaminergic neurons, without generating fibrillar inclusions. We found reversibly reduced levels of dopamine and metabolites in the OB, suggesting an impact of A30P alpha-syn on olfactory neurotransmitter content. We further showed that mutant A30P expression led to neurodegenerative changes on an ultrastructural level and a behaviorally hyperactive response correlated with novelty, odor processing and stress associated with an increased dopaminergic tone in midbrain regions. Our present data indicate that mutant (A30P) alpha-syn is directly implicated in reduction of dopamine signaling in OB interneurons, which mediates further alterations in brain regions without transgenic expression leading functionally to a hyperactive response. These modulations of neurotransmission may underlie in part some of the early neuropsychiatric symptoms in PD preceding dysfunction of the nigrostriatal dopaminergic system. [less ▲]

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See detailIdentification and functional dissection of localization signals within ataxin-3.
Antony, Paul UL; Mäntele, Simone; Mollenkopf, Phillip et al

in Neurobiology of Disease (2009), 36(2), 280-92

Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD) belongs to a group of autosomal dominant neurodegenerative diseases, which are caused by the expansion of a polyglutamine repeat in the ... [more ▼]

Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD) belongs to a group of autosomal dominant neurodegenerative diseases, which are caused by the expansion of a polyglutamine repeat in the affected protein, in this case ataxin-3. Ataxin-3 is mainly localized in the cytoplasm; however, one hallmark of SCA3 is the formation of ataxin-3-containing protein aggregates in the nucleus of neurons. Currently, it is not known how mutant ataxin-3 translocates into the nucleus. We performed localization assays of recently proposed and novel potential signals, functionally confirmed the activity of a nuclear localization signal, identified two novel nuclear export signals (NES 77 and NES 141), and determined crucial amino acids. In addition, we demonstrate the relevance of the identified signals for the intracellular localization of the N- and C-terminus of ataxin-3. Our findings stress the importance of investigating the mechanisms, which influence the intracellular distribution of ataxin-3 during the pathogenesis of SCA3. [less ▲]

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