Biology subjects

van Hilten, J. J.

Publications and source records attributed to van Hilten, J. J..

6 recordsLinked to original sources

bioRxiv2020

Transcriptomic signatures associated with regional cortical thickness changes in Parkinson's disease

Cortical atrophy is a common manifestation in Parkinsons disease, particularly in later disease stages. Here, we investigated patterns of cortical thickness using T1-weighted anatomical MRI data of 149 Parkinsons disease patients and 369 controls. To elucidate the molecular underpinnings of cortical thickness changes in Parkinsons disease, we performed an integrated analysis of brain-wide healthy transcriptomic data from the Allen Human Brain Atlas and neuroimaging features. For this purpose, we used partial least squares regression to identify gene expression patterns correlated with cortical thickness changes. In addition, we identified gene expression patterns underlying the relationship between cortical thickness and clinical domains of Parkinsons disease. Our results show that genes whose expression in the healthy brain is associated with cortical thickness changes in Parkinsons disease are enriched in biological pathways related to sumoylation, regulation of mitotic cell cycle, mitochondrial translation, DNA damage responses, and ER-Golgi traffic. The associated pathways were highly related to each other and all belong to cellular maintenance mechanisms. The expression of genes within most pathways was negatively correlated with cortical thickness changes, showing higher expression in regions associated with decreased cortical thickness (atrophy). On the other hand, sumoylation pathways were positively correlated with cortical thickness changes, showing higher expression in regions with increased cortical thickness (hypertrophy). Our findings suggest that alterations in the balanced interplay of these mechanisms play a role in changes of cortical thickness in Parkinsons disease and possibly influence motor and cognitive functions.

bioinformatics↗

bioRxiv2019

Cholinergic circuit genes in the healthy brain are differentially expressed in regions that exhibit gray matter loss in Parkinson's disease

Structural covariance networks are able to identify functionally organized brain regions by gray matter volume covariance. In Parkinsons disease, the posterior cingulate network and anterior cingulate network showed decreased gray matter and therefore we examined the underlying molecular processes of these anatomical networks in the healthy brain. Whole brain transcriptomics from post-mortem samples from healthy adults, revealed upregulation of genes associated with serotonin, GPCR, GABA, glutamate, and RAS signaling pathways in these PD-related regions. Our results also suggest involvement of the cholinergic circuit, in which genes NPPA, SOSTDC1, and TYRP1 may play a protective role. Furthermore, both networks were associated with memory and neuropsychiatric disorders that overlap with Parkinsons disease symptoms. The identified genes and pathways contribute to healthy functions of the posterior and anterior cingulate networks and disruptions to these functions may in turn contribute to the pathological and clinical events observed in Parkinsons disease.

bioinformatics↗

bioRxiv2019

Genetic modifiers of risk and age at onset in GBA associated Parkinson disease and Lewy body dementia

Parkinsons disease (PD) is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of PD, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as PD and Lewy body dementia (LBD). These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known PD risk variants.\n\nUsing multiple, large case-control datasets, totalling 217,165 individuals (22,757 PD cases, 13,431 PD proxy cases, 622 LBD cases and 180,355 controls), we identified 1,772 PD cases, 711 proxy cases and 7,624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent PD-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall PD genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S neurons were shown to have decreased Cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated PD risk and age at onset and demonstrate that variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have important implications for selection of GBA carriers for therapeutic interventions.

genetics↗

bioRxiv2019

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

The molecular mechanisms underlying the caudal-to-rostral progression of Lewy body pathology in Parkinsons disease (PD) remain poorly understood. Here, we aimed to unravel transcriptomic signatures across brain regions involved in Braak Lewy body stages in non-neurological controls and PD donors. Using human postmortem brain datasets of non-neurological adults from the Allen Human Brain Atlas, we identified expression patterns related to PD progression, including genes found in PD genome-wide associations studies: SNCA, ZNF184, BAP1, SH3GL2, ELOVL7, and SCARB2. We confirmed these patterns in two datasets of non-neurological subjects (Genotype-Tissue Expression project and UK Brain Expression Consortium) and found altered patterns in two datasets of PD patients. Additionally, co-expression analysis across vulnerable regions identified two modules associated with dopamine synthesis, the motor and immune system, blood-oxygen transport, and contained microglial and endothelial cell markers, respectively. Alterations in genes underlying these region-specific functions may contribute to the selective regional vulnerability in PD brains.

neuroscience↗

bioRxiv2018

Parkinson disease age of onset GWAS: defining heritability, genetic loci and a-synuclein mechanisms

Increasing evidence supports an extensive and complex genetic contribution to Parkinsons disease (PD). Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age of onset are largely unknown. Here we performed an age of onset GWAS based on 28,568 PD cases. We estimated that the heritability of PD age of onset due to common genetic variation was ~0.11, lower than the overall heritability of risk for PD (~0.27) likely in part because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni corrected significant effect at other known PD risk loci, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. In addition, we identified that GBA coding variant carriers had an earlier age of onset compared to non-carriers. Notably, SNCA, TMEM175, SCARB2, BAG3 and GBA have all been shown to either directly influence alpha-synuclein aggregation or are implicated in alpha-synuclein aggregation pathways. Remarkably, other well-established PD risk loci such as GCH1, MAPT and RAB7L1/NUCKS1 (PARK16) did not show a significant effect on age of onset of PD. While for some loci, this may be a measure of power, this is clearly not the case for the MAPT locus; thus genetic variability at this locus influences whether but not when an individual develops disease. We believe this is an important mechanistic and therapeutic distinction. Furthermore, these data support a model in which alpha-synuclein and lysosomal mechanisms impact not only PD risk but also age of disease onset and highlights that therapies that target alpha-synuclein aggregation are more likely to be disease-modifying than therapies targeting other pathways.

genetics↗

bioRxiv2018

Peripheral mitochondrial function correlates with clinical severity in idiopathic Parkinson’s disease

BackgroundParkinson disease is an intractable disorder with heterogeneous clinical presentation that may reflect different underlying pathogenic mechanisms. Surrogate indicators of pathogenic processes correlating with clinical measures may assist in better patients stratification. Mitochondrial function - which is impaired in and central to PD pathogenesis - may represent one of such surrogate indicators.\n\nMethodsMitochondrial function was assessed by respirometry experiment in fibroblasts derived from idiopathic patients (n=47) in normal conditions and in experimental settings that do not permit glycolysis and therefore force energy production through mitochondrial function. Respiratory parameters and clinical measures were correlated with bivariate analysis. Machine learning based classification and regression trees were used to classify patients on the basis of biochemical and clinical measures. Effects of mitochondrial respiration on alpha-synuclein stress was assessed monitoring the protein phosphorylation in permitting versus restrictive glycolysis conditions.\n\nResultsBioenergetics properties in peripheral fibroblasts correlate with clinical measures in idiopathic patients and correlation is stronger with predominantly non-dopaminergic signs. Bioenergetics analysis under metabolic stress, in which energy is produced solely by mitochondria, shows that patients fibroblasts can augment respiration, therefore indicating that mitochondrial defects are reversible. Forcing energy production through mitochondria, however, favors alpha-synuclein stress in different cellular experimental systems. Machine learning-based classification identified different groups of patients in which increasing disease severity parallels higher mitochondrial respiration.\n\nConclusionSuppression of mitochondrial activity in Parkinson disease may be an adaptive strategy to cope with concomitant pathogenic factors. Moreover, mitochondrial measures are potential biomarkers to follow disease progression.

neuroscience↗