Altered Expression of Brain Proteinase-Activated Receptor-2, Trypsin-2 and Serpin Proteinase Inhibitors in Parkinson’s Disease

Hurley, Michael J.; Durrenberger, Pascal F.; Gentleman, Steve; Walls, Andrew F.; Dexter, David T.

doi:10.1007/s12031-015-0576-8

Cited by 25 publications

(17 citation statements)

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“…On the other hand, prodromal alterations in motor cortex plasticity are supported by pathological investigations on Ca 2+ channels, which are critical in the regulation of cortical excitability and plasticity (Wankerl et al, 2010;Verhoog et al, 2013;Weise et al, 2017). Specifically, recent postmortem studies show increased expression of L-type voltagegated Ca 2+ channels in the primary motor cortex at least as early as Braak's stages III-IV (Hurley et al, 2013(Hurley et al, , 2015b, and molecular alterations in motor cortical areas have also been reported in incidental Lewy body disease at Braak's stages I-II (Hurley et al, 2015a;Santpere et al, 2018). Motor cortical areas thus seem to be altered well before the appearance of cortical Lewy pathology (Braak's stages V-VI) and before the onset of motor features in PD.…”

Section: Evidence For Primary Cortical Involvement In Parkinson's Dismentioning

confidence: 95%

A Cortical Pathogenic Theory of Parkinson’s Disease

Foffani

Obeso

2018

Neuron

125

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In Parkinson's disease, the progressive neurodegeneration of nigrostriatal dopaminergic neurons in the substantia nigra pars compacta (SNc) is associated with classic motor features, which typically have a focal onset. Since a defined somatotopic arrangement in the SNc has not been recognized, this focal motor onset is unexplained and hardly justified by current pathogenic theories of bottom-up disease progression (Braak's hypothesis, prionopathy). Here we propose that corticostriatal activity may represent a critical somatotopic "stressor" for nigrostriatal terminals, ultimately driving retrograde nigrostriatal degeneration and leading to focal motor onset and progression of Parkinson's disease. As a pathogenic mechanism, corticostriatal activity may promote secretion of striatal extracellular alpha-synuclein, favoring its pathological aggregation at vulnerable dopaminergic synapses. A similar pathogenic process may occur at corticofugal projections to the medulla oblongata and other vulnerable structures, thereby contributing to the bottom-up progression of Lewy pathology. This cortical pathogenesis may co-exist with bottom-up mechanisms, adding an integrative top-down perspective to the quest for the factors that impinge upon the vulnerability of dopaminergic cells in the onset and progression of Parkinson's disease.

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Section: Evidence For Primary Cortical Involvement In Parkinson's Dismentioning

confidence: 95%

A Cortical Pathogenic Theory of Parkinson’s Disease

Foffani

Obeso

2018

Neuron

125

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“…We validated the relevance of the identified BRGs to PD progression with two datasets of non-neurological controls (Genotype-Tissue Expression project (GTEx) 19 and UK Brain Expression Consortium (UKBEC) 20 ) and two datasets of PD donors. We found altered expression patterns in patients with PD and incidental Lewy body disease (iLBD), who are assumed to represent the pre-clinical stage of PD 11,21 . In non-neurological brains from the AHBA, we further identified modules of co-expressed genes across Braak LB stage involved regions, and characterized them functionally by assessing their enrichment for cell-type markers, gene ontology (GO)-terms, and disease-associated genes.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Keo

Mahfouz

Ingrassia

et al. 2019

Preprint

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25The molecular mechanisms underlying the caudal-to-rostral progression of Lewy body pathology in 26Parkinson's disease (PD) remain poorly understood. Here, we aimed to unravel transcriptomic signatures 27 across brain regions involved in Braak Lewy body stages in non-neurological controls and PD donors. 28Using human postmortem brain datasets of non-neurological adults from the Allen Human Brain Atlas, we 29 identified expression patterns related to PD progression, including genes found in PD genome-wide 30 associations studies: SNCA, ZNF184, BAP1, SH3GL2, ELOVL7, and SCARB2. We confirmed these 31 patterns in two datasets of non-neurological subjects (Genotype-Tissue Expression project and UK Brain 32 Expression Consortium) and found altered patterns in two datasets of PD patients. Additionally, co-33 expression analysis across vulnerable regions identified two modules associated with dopamine 34 synthesis, the motor and immune system, blood-oxygen transport, and contained microglial and 35 endothelial cell markers, respectively. Alterations in genes underlying these region-specific functions may 36 contribute to the selective regional vulnerability in PD brains. 37 38 3 Background 39 Parkinson's disease (PD) is characterized by a temporal caudal-rostral progression of Lewy body (LB) 40 pathology across a selected set of nuclei in the brain 1 . The distribution pattern of LB pathology is divided 41 into six Braak stages based on accumulation of the protein α-synucleinthe main component of LBs and 42 Lewy neuritesin the brainstem, limbic and neocortical regions 1 . Different hypotheses have been 43 brought forward to explain the evolving LB pathology across the brain, including: retrograde transport of 44 pathological α-synuclein via neuroanatomical networks, α-synuclein's prion-like behavior, and cell-or 45 region-autonomous factors 2,3 . Yet, the mechanisms underlying the selective vulnerability of brain regions 46 to LB pathology remains poorly understood, limiting the ability to diagnose and treat PD. 47 Multiplications of the SNCA gene encoding α-synuclein are relatively common in autosomal dominant PD 48and SNCA dosage has been linked to the severity of PD 4,5 . For other PD-associated variants, e.g. GBA 49and LRRK2, their role in progressive α-synuclein accumulation is less clear, although they have been 50 associated with mitochondrial (dys)function and/or protein degradation pathways [6][7][8] . On the other hand, 51 transcriptomic changes between PD and non-neurological controls of selected brain regions, e.g. the 52 substantia nigra, have identified several molecular mechanisms underlying PD pathology, including 53 synaptic vesicle endocytosis [9][10][11] . However, post-mortem human brain tissue of well-characterized PD 54 patients and controls is scarce, usually focuses on a select number of brain regions, and have a limited 55 coverage of patients with different Braak LB stages, resulting in low concordance of findings across 56 different studies 12 . 57Spatial gene expression patterns in the human ...

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“…We validated our findings in two independent non-neurological datasets (the Genotype-Tissue Expression project (GTEx) 19 and UK Brain Expression Consortium (UKBEC) 20 ). Further, we showed that Braak stage-related genes (BRGs) are indeed progressively disrupted in patients with incidental Lewy body disease (iLBD; assumed to represent the pre-clinical stage of PD 11,21 ) and PD. The observed transcriptomic signatures of vulnerable brain regions pointed towards the dopamine biosynthetic process and oxygen transport that were highly expressed in brain regions related to the preclinical stages of PD.…”

mentioning

confidence: 99%

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

et al. 2020

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The molecular mechanisms underlying caudal-to-rostral progression of Lewy body pathology in Parkinson's disease remain poorly understood. Here, we identified transcriptomic signatures across brain regions involved in Braak Lewy body stages in non-neurological adults from the Allen Human Brain Atlas. Among the genes that are indicative of regional vulnerability, we found known genetic risk factors for Parkinson's disease: SCARB2, ELOVL7, SH3GL2, SNCA, BAP1, and ZNF184. Results were confirmed in two datasets of nonneurological subjects, while in two datasets of Parkinson's disease patients we found altered expression patterns. Co-expression analysis across vulnerable regions identified a module enriched for genes associated with dopamine synthesis and microglia, and another module related to the immune system, blood-oxygen transport, and endothelial cells. Both were highly expressed in regions involved in the preclinical stages of the disease. Finally, alterations in genes underlying these region-specific functions may contribute to the selective regional vulnerability in Parkinson's disease brains.

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Altered Expression of Brain Proteinase-Activated Receptor-2, Trypsin-2 and Serpin Proteinase Inhibitors in Parkinson’s Disease

Cited by 25 publications

References 50 publications

A Cortical Pathogenic Theory of Parkinson’s Disease

A Cortical Pathogenic Theory of Parkinson’s Disease

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

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