Evidence for Immune Response, Axonal Dysfunction and Reduced Endocytosis in the Substantia Nigra in Early Stage Parkinson’s Disease

Dijkstra, Anke A.; Ingrassia, Angela; Menezes, Renée X. de; Kesteren, Ronald E. van; Rozemüller, Annemieke; Heutink, Peter; Berg, Wilma D. J. van de

doi:10.1371/journal.pone.0128651

Cited by 134 publications

(127 citation statements)

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“…This observation is similar to those made in another transgenic α-syn model [67], and indicates that the earliest response to the transgenic abnormal α-syn challenge is at the gene expression level. Interestingly, Dijkstra et al [22] reported a lower number of DEGs in SN from patients late Braak stages (3 and up) compared to patients at an early Braak stage (1)(2). Similarly, in another study, more altered pathways were observed in incidental Lewy Body Disease compared to PD [80].…”

Section: Key Observations In the Transcriptional Profiling Of The Bacmentioning

confidence: 88%

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Hendrickx

Garcia

Ashrafi

et al. 2020

Preprint

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Understanding Parkinson's disease (PD) in particular in its earliest phases is important for diagnosis and treatment. However, human brain samples are collected post-mortem, reflecting mainly end stage disease. Because brain samples of mouse models can be collected at any stage of the disease process, they are useful to investigate PD progression. Here, we compare ventral midbrain transcriptomics profiles from α-synuclein transgenic mice with a progressive, early PD-like striatum neurodegeneration across different ages using pathway, gene set and network analysis methods. Our study uncovers statistically significant altered genes across ages and between genotypes with known, suspected or unknown function in PD pathogenesis and key pathways associated with disease progression. Among those are genotype-dependent alterations associated with synaptic plasticity, neurotransmission, as well as mitochondria-related genes and dysregulation of lipid metabolism. Age-dependent changes were among others observed in neuronal and synaptic activity, calcium homeostasis, and membrane receptor signaling pathways, many of which linked to G-protein coupled receptors. Most importantly, most changes occurred before neurodegeneration was detected in this model, which points to a sequence of gene expression events that may be relevant for disease initiation and progression. It is tempting to speculate that molecular changes similar to those changes observed in our model happen in midbrain dopaminergic neurons before they start to degenerate. In other words, we believe we have uncovered molecular changes that accompany the progression from preclinical to early PD. 1/30 models provide a useful means to investigate PD-associated molecular changes, in particular those preceding nigro-striatal degeneration. The elucidation of such early changes can shed light into disease causation and drivers of disease progression, thus in turn pointing to novel targets for intervention as well as biomarkers [16,45].Whole transcriptome analysis enables to compare thousands of genes between two or more groups [9], and provides a valuable method for identifying coordinated changes in gene expression patterns that are not captured by single-gene or protein measurement approaches [59]. Despite of these advantages, only a limited amount of studies have used transcriptomics on α-synuclein-based transgenic mouse models for PD [13, 67, 71-73, 94, 98]. Alpha-synuclein, a pre-synaptic protein believed to be a moderator of the synaptic vesicle cycle, is a major component of Lewy bodies [87]. In addition, mutations or multiplications in its genes leads to familiar forms of PD [26,46]. Transcriptomics studies on α-synuclein-based transgenic mouse models for PD have only looked at differentially expressed genes (DEGs) in relation to pre-defined cellular pathways or gene sets from public annotation databases [13,67,[71][72][73]94]. Most of them used only one [71][72][73] or two age groups [13,67,94,98] of the mouse model for their analyses, and some of them were perform...

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Section: Key Observations In the Transcriptional Profiling Of The Bacmentioning

confidence: 88%

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Hendrickx

Garcia

Ashrafi

et al. 2020

Preprint

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“…Recognition of an important role of neuroinflammation in human PD and in the α-syn PFF model has been growing. 66,[87][88][89][90][91][92][93][94][95] In addition, previous results demonstrated that dieldrin exposure exacerbates MPTP-induced increases in expression of glial fibrillary acidic protein (GFAP) levels in the striatum, suggesting that dieldrin exposure leads to a greater neuroinflammatory response to a second insult. While we were unable to test expression of neuroinflammatory genes after the application of PFFs, we did identify dieldrin-induced changes in the expression of neuroinflammatory genes.…”

Section: Dieldrin Induced Sex-specific Effects In the Nigrostriatal Pmentioning

confidence: 99%

Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-synuclein-preformed fibril-induced toxicity and motor deficits

Gezer

Kochmanski

VanOeveren

et al. 2020

Preprint

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Highlights• Developmental dieldrin exposure increases α-syn-PFF-induced motor deficits • Developmental dieldrin exposure increases PFF-induced deficits in DA handling • Developmental dieldrin exposure does not affect PFF-induced loss of nigral neurons • This is a novel paradigm modeling how environmental factors increase risk of PD • Female mice show PFF-induced pathology, but no PFF-induced motor deficits. AbstractHuman and animal studies have shown that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson's disease (PD). Previous work showed that developmental dieldrin exposure increased neuronal susceptibility to MPTP toxicity in male C57BL/6 mice, possibly via changes in dopamine (DA) packaging and turnover. However, the relevance of the MPTP model to PD pathophysiology has been questioned. We therefore studied dieldrin-induced neurotoxicity in the α-synuclein (α-syn)-preformed fibril (PFF) model, which better reflects the α-syn pathology and toxicity observed in PD pathogenesis. Specifically, we used a "two-hit" model to determine whether developmental dieldrin exposure increases susceptibility to α-syn PFF-induced synucleinopathy. Dams were fed either dieldrin (0.3 mg/kg, every 3-4 days) or vehicle corn oil starting 1 month prior to breeding and continuing through weaning of pups at postnatal day 22. At 12 weeks of age, male and female offspring received intrastriatal PFF or control saline injections. Consistent with the male-specific increased susceptibility to MPTP, our results demonstrate that developmental dieldrin exposure exacerbates PFF-induced toxicity in male mice only. Specifically, in male offspring, dieldrin exacerbated PFF-induced motor deficits on the challenging beam and increased DA turnover in the striatum 6 months after PFF injection. However, male offspring showed neither exacerbation of phosphorylated α-syn (pSyn) aggregation in the substantia nigra (SN) at 1 or 2 months post-PFF injection, nor exacerbation of PFF-induced TH and NeuN loss in the SN 6 months post-PFF injection. Collectively, these data indicate that developmental dieldrin exposure produces a male-specific increase in neuronal vulnerability to synucleinopathy. This sex-specific result is consistent with both previous work in the MPTP model, our previously reported sex-specific effects of this exposure paradigm on the male and female epigenome, and the higher prevalence and more severe course of PD in males. The novel two-hit environmental toxicant/PFF exposure paradigm established in this project can be used to explore the mechanisms by which other PD-related exposures alter neuronal vulnerability to synucleinopathy in sporadic PD. KeywordsParkinson's, pesticide, synuclein, neurotoxicity, neuroinflammation, sex differences resistant. Over time, the α-syn aggregates progressively compact and eventually lead to neuronal degeneration. 38,39,45,46 Thus, the intrastriatal injection of α-syn PFFs can be used to model pathological synucleinopathy and nigrostriatal toxicity in mice. Here...

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“…On the other hand, transcriptomic changes between PD and non-neurological controls of selected brain regions, e.g. the substantia nigra, have identified several molecular mechanisms underlying PD pathology, including synaptic vesicle endocytosis 9–11 . However, post-mortem human brain tissue of well-characterized PD patients and controls is scarce, usually focuses on a select number of brain regions, and have a limited coverage of patients with different Braak LB stages, resulting in low concordance of findings across different studies 12 .…”

Section: Introductionmentioning

confidence: 99%

“…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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Evidence for Immune Response, Axonal Dysfunction and Reduced Endocytosis in the Substantia Nigra in Early Stage Parkinson’s Disease

Cited by 134 publications

References 58 publications

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

A new synuclein-transgenic mouse model for early Parkinson’s reveals molecular features of preclinical disease

Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-synuclein-preformed fibril-induced toxicity and motor deficits

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

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