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Glucocerebrosidase mRNA is Diminished in Brain of Lewy Body Diseases and Changes with Disease Progression in Blood.

ABSTRACT: Parkinson disease (PD) and dementia with Lewy bodies (DLB) are Lewy body diseases characterized by abnormal alpha-synuclein deposits and overlapping pathological features in the brain. Several studies have shown that glucocerebrosidase (GBA) deficiency is involved in the development of LB diseases. Here, we aimed to find out if this deficiency starts at the transcriptional level, also involves alternative splicing, and if GBA expression changes in brain are also detectable in blood of patients with LB diseases. The expression of three GBA transcript variants (GBAtv1, GBAtv2 and GBAtv5) was analyzed in samples from 20 DLB, 25 PD and 17 control brains and in blood of 20 DLB, 26 PD patients and 17 unaffected individuals. Relative mRNA expression was determined by real-time PCR. Expression changes were evaluated by the ??Ct method. In brain, specific expression profiles were identified in the temporal cortex of DLB and in the caudate nucleus of PD. In blood, significant GBA mRNA diminution was found in both DLB and PD patients. Early PD and early-onset DLB patients showed lowest GBA levels which were normal in PD patients with advanced disease and DLB patients who developed disease after 70 years of age. In conclusion, disease group specific GBA expression profiles were found in mostly affected areas of LBD. In blood, GBA expression was diminished in LB diseases, especially in patients with early onset DLB and in patients with early PD. Age of disease onset exerts an opposite effect on GBA expression in DLB and PD.

SUBMITTER: Perez-Roca L

PROVIDER: S-EPMC5963343 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Glucocerebrosidase mRNA is Diminished in Brain of Lewy Body Diseases and Changes with Disease Progression in Blood.

Perez-Roca Laia L Adame-Castillo Cristina C Campdelacreu Jaume J Ispierto Lourdes L Vilas Dolores D Rene Ramon R Alvarez Ramiro R Gascon-Bayarri Jordi J Serrano-Munoz Maria A MA Ariza Aurelio A Beyer Katrin K

Aging and disease 20180401 2

Parkinson disease (PD) and dementia with Lewy bodies (DLB) are Lewy body diseases characterized by abnormal alpha-synuclein deposits and overlapping pathological features in the brain. Several studies have shown that glucocerebrosidase (GBA) deficiency is involved in the development of LB diseases. Here, we aimed to find out if this deficiency starts at the transcriptional level, also involves alternative splicing, and if GBA expression changes in brain are also detectable in blood of patients w ...[more]

PMID: 29896411

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Project description:Background Lewy body diseases (LBDs) feature deficiency of the sympathetic neurotransmitter norepinephrine in the left ventricular myocardium and sympathetic intra-neuronal deposition of the protein alpha-synuclein (αS). LBDs therefore are autonomic synucleinopathies. Computational modeling has revealed multiple functional abnormalities in residual myocardial sympathetic noradrenergic nerves in LBDs, including decreased norepinephrine synthesis, vesicular storage, and recycling. We report an extended model that enables predictions about the progression of LBDs and effects of genetic predispositions and treatments on that progression. Methods and Results The model combines cardiac sympathetic activation with autotoxicity mediated by the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde. We tested the model by its ability to predict longitudinal empirical data based on cardiac sympathetic neuroimaging, effects of genetic variations related to particular intra-neuronal reactions, treatment by monoamine oxidase inhibition to decrease 3,4-dihydroxyphenylacetaldehyde production, and post-mortem myocardial tissue contents of catecholamines and αS. The new model generated a triphasic decline in myocardial norepinephrine content. This pattern was confirmed by empirical data from serial cardiac 18F-dopamine positron emission tomographic scanning in patients with LBDs. The model also correctly predicted empirical data about effects of genetic variants and monoamine oxidase inhibition and about myocardial levels of catecholamines and αS. Conclusions The present computational model predicts a triphasic decline in myocardial norepinephrine content as LBDs progress. According to the model, disease-modifying interventions begun at the transition from the first to the second phase delay the onset of symptomatic disease. Computational modeling coupled with biomarkers of preclinical autonomic synucleinopathy may enable early detection and more effective treatment of LBDs.

Project description:Neurodegenerative diseases are a class of chronic and complex disorders featuring progressive loss of neurons in distinct brain areas. The mechanisms responsible for the disease progression in neurodegeneration are not fully illustrated. In this observational study, we have examined diverse biochemical parameters in the caudate and putamen of patients with Lewy body diseases (LBDs) and Alzheimer disease (AD), shedding some light on the involvement of oxidative damage and neuroinflammation in advanced neurodegeneration. We performed Spearman and Mantel-Cox analyses to investigate how oxidative stress and neuroinflammation exert comprehensive effects on disease progression and survival. Disease progression in LBDs correlated positively with poly (ADP-Ribose) and triggering receptors expressed on myeloid cell 2 levels in the striatum of LBD cohorts, indicating that potential parthanatos was a dominant feature of worsening disease progression and might contribute to switching microglial inflammatory phenotypes. Disease progression in AD corresponds negatively with 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and myeloperoxidase concentrations in the striatum, suggesting that possible mitochondria dysfunction may be involved in the progression of AD via a mechanism of β-amyloid entering the mitochondria and subsequent free radicals generation. Patients with lower striatal 8-oxo-dG and myeloperoxidase levels had a survival advantage in AD. The age of onset also affected disease progression. Tissue requests for the postmortem biochemistry, genetics, and autoradiography studies were approved by the Washington University Alzheimer's Disease Research Center (ADRC) Biospecimens Committee (ethics approval reference number: T1705, approval date: August 6, 2019). Recombinant DNA and Hazardous Research Materials were approved by the Washington University Environmental Health & Safety Biological Safety Committee (approval code: 3739, approval date: February 25, 2020). Radioactive Material Authorization was approved by the Washington University Environmental Health & Safety Radiation Safety Committee (approval code: 1056, approval date: September 18, 2019).

Project description:OBJECTIVE:Regional cortical thinning in dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD) may underlie some aspect of their clinical impairments; cortical atrophy likely reflects extensive Lewy body pathology with alpha-synuclein deposits, as well as associated Alzheimer's disease co-pathologies, when present. Here we investigated the topographic distribution of cortical thinning in these Lewy body diseases compared to cognitively normal PD and healthy non-PD control subjects, explored the association of regional thinning with clinical features and evaluated the impact of amyloid deposition. METHODS:Twenty-one participants with dementia with Lewy bodies (DLB), 16 with Parkinson disease (PD) - associated cognitive impairment (PD-MCI and PDD), and 24 cognitively normal participants with PD underwent MRI, PiB PET, and clinical evaluation. Cortical thickness across the brain and in regions of interest (ROIs) was compared across diagnostic groups and across subgroups stratified by amyloid status, and was related to clinical and cognitive measures. RESULTS:DLB and PD-impaired groups shared a similar distribution of cortical thinning that included regions characteristic of AD, as well as the fusiform, precentral, and paracentral gyri. Elevated PiB retention in DLB and PD-impaired but not in PD-normal participants was associated with more extensive and severe cortical thinning, in an overlapping topography that selectively affected the medial temporal lobe in DLB participants. In DLB, greater thinning in AD signature and fusiform regions was associated with greater cognitive impairment. CONCLUSIONS:The pattern of cortical thinning is similar in DLB and PD-associated cognitive impairment, overlapping with and extending beyond AD signature regions to involve fusiform, precentral, and paracentral regions. Cortical thinning in AD signature and fusiform regions in these diseases reflects cognitive impairment and is markedly accentuated by amyloid co-pathology. Further work will be required to determine whether the distinct topography of cortical thinning in DLB and PD-associated cognitive impairment might have value as a diagnostic and/ or outcome biomarker in clinical trials.

Project description:Autosomal dominant variants in LRP10 have been identified in patients with Lewy body diseases (LBDs), including Parkinson's disease (PD), Parkinson's disease-dementia (PDD), and dementia with Lewy bodies (DLB). Nevertheless, there is little mechanistic insight into the role of LRP10 in disease pathogenesis. In the brains of control individuals, LRP10 is typically expressed in non-neuronal cells like astrocytes and neurovasculature, but in idiopathic and genetic cases of PD, PDD, and DLB, it is also present in α-synuclein-positive neuronal Lewy bodies. These observations raise the questions of what leads to the accumulation of LRP10 in Lewy bodies and whether a possible interaction between LRP10 and α-synuclein plays a role in disease pathogenesis. Here, we demonstrate that wild-type LRP10 is secreted via extracellular vesicles (EVs) and can be internalised via clathrin-dependent endocytosis. Additionally, we show that LRP10 secretion is highly sensitive to autophagy inhibition, which induces the formation of atypical LRP10 vesicular structures in neurons in human-induced pluripotent stem cells (iPSC)-derived brain organoids. Furthermore, we show that LRP10 overexpression leads to a strong induction of monomeric α-synuclein secretion, together with time-dependent, stress-sensitive changes in intracellular α-synuclein levels. Interestingly, patient-derived astrocytes carrying the c.1424 + 5G > A LRP10 variant secrete aberrant high-molecular-weight species of LRP10 in EV-free media fractions. Finally, we show that this truncated patient-derived LRP10 protein species (LRP10splice) binds to wild-type LRP10, reduces LRP10 wild-type levels, and antagonises the effect of LRP10 on α-synuclein levels and distribution. Together, this work provides initial evidence for a possible functional role of LRP10 in LBDs by modulating intra- and extracellular α-synuclein levels, and pathogenic mechanisms linked to the disease-associated c.1424 + 5G > A LRP10 variant, pointing towards potentially important disease mechanisms in LBDs.

Dataset Information

Glucocerebrosidase mRNA is Diminished in Brain of Lewy Body Diseases and Changes with Disease Progression in Blood.

Publications

Glucocerebrosidase mRNA is Diminished in Brain of Lewy Body Diseases and Changes with Disease Progression in Blood.

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