scholarly journals Reduced sphingolipid hydrolase activities, substrate accumulation and ganglioside decline in Parkinson’s disease

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Mylene Huebecker ◽  
Elizabeth B. Moloney ◽  
Aarnoud C. van der Spoel ◽  
David A. Priestman ◽  
Ole Isacson ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Strong Predictor ◽  
Brain Regions ◽  
Lysosomal Storage ◽  
Lysosomal Hydrolases ◽  
Genetic Risks ◽  
Normal Phase Hplc ◽  
First Time

Abstract Background Haploinsufficiency in the Gaucher disease GBA gene, which encodes the lysosomal glucocerebrosidase GBA, and ageing represent major risk factors for developing Parkinson’s disease (PD). Recently, more than fifty other lysosomal storage disorder gene variants have been identified in PD, implicating lysosomal dysfunction more broadly as a key risk factor for PD. Despite the evidence of multiple lysosomal genetic risks, it remains unclear how sphingolipid hydrolase activities, other than GBA, are altered with ageing or in PD. Moreover, it is not fully known if levels of glycosphingolipid substrates for these enzymes change in vulnerable brain regions of PD. Finally, little is known about the levels of complex gangliosides in substantia nigra which may play a significant role in ageing and PD. Methods To study sphingolipid hydrolase activities and glycosphingolipid expression in ageing and in PD, two independent cohorts of human substantia nigra tissues were obtained. Fluorescent 4-methylumbelliferone assays were used to determine multiple enzyme activities. The lysosomal GBA and non-lysosomal GBA2 activities were distinguished using the inhibitor NB-DGJ. Sensitive and quantitative normal-phase HPLC was performed to study glycosphingolipid levels. In addition, glycosphingolipid levels in cerebrospinal fluid and serum were analysed as possible biomarkers for PD. Results The present study demonstrates, in two independent cohorts of human post-mortem substantia nigra, that sporadic PD is associated with deficiencies in multiple lysosomal hydrolases (e.g. α-galactosidase and β-hexosaminidase), in addition to reduced GBA and GBA2 activities and concomitant glycosphingolipid substrate accumulation. Furthermore, the data show significant reductions in levels of complex gangliosides (e.g. GM1a) in substantia nigra, CSF and serum in ageing, PD, and REM sleep behaviour disorder, which is a strong predictor of PD. Conclusions These findings conclusively demonstrate reductions in GBA activity in the parkinsonian midbrain, and for the first time, reductions in the activity of several other sphingolipid hydrolases. Furthermore, significant reductions were seen in complex gangliosides in PD and ageing. The diminished activities of these lysosomal hydrolases, the glycosphingolipid substrate accumulation, and the reduced levels of complex gangliosides are likely major contributors to the primary development of the pathology seen in PD and related disorders with age.

scholarly journals Neuroinflammation and protein pathology in Parkinson’s disease dementia

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Antonina Kouli ◽  
Marta Camacho ◽  
Kieren Allinson ◽  
Caroline H. Williams-Gray
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
T Lymphocytes ◽  
Substantia Nigra ◽  
Amyloid Β ◽  
Brain Regions ◽  
Parkinson’S Disease Dementia ◽  
Activated Microglia ◽  
Cell Counts ◽  
The Brain

AbstractParkinson’s disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer’s disease-type pathology. Whilst immune activation is well-described in Parkinson’s disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.

scholarly journals A pH-eQTL interaction at the RIT2-SYT4 Parkinson's disease risk locus in the substantia nigra

2020 ◽  
Author(s):  
Sejal Patel ◽  
Derek Howard ◽  
Leon French
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Human Brain ◽  
Disease Risk ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Postmortem Human Brain ◽  
Increased Risk

BACKGROUND: Parkinson's disease (PD) causes severe motor and cognitive disabilities that result from the progressive loss of dopamine neurons in the substantia nigra. The rs12456492 variant in the RIT2 gene has been repeatedly associated with increased risk for Parkinson's disease. From a transcriptomic perspective, a meta-analysis found that RIT2 gene expression is correlated with pH in the human brain. OBJECTIVE: To assess pH associations at the RIT2-SYT4 locus. METHODS: Linear models to examine two datasets that assayed rs12456492, gene expression, and pH in the postmortem human brain. RESULTS: Using the BrainEAC dataset, we replicate the positive correlation between RIT2 gene expression and pH in the human brain. Furthermore, we found that the relationship between expression and pH is influenced by rs12456492. When tested across ten brain regions, this interaction is specifically found in the substantia nigra. A similar association was found for the co-localized SYT4 gene. In addition, SYT4 associations are stronger in a combined model with both genes, and the SYT4 interaction appears to be specific to males. In the GTEx dataset, the pH associations involving rs12456492 and expression of either SYT4 and RIT2 was not seen. This null finding may be due to the short postmortem intervals (PMI) of the GTEx tissue samples. In the BrainEAC data, we tested the effect of PMI and only observed the interactions in the longer PMI samples. CONCLUSIONS: These previously unknown associations suggest novel mechanistic roles for rs12456492, RIT2, and SYT4 in the regulation of pH in the substantia nigra.

scholarly journals Systemic α-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson’s disease

2019 ◽  
Author(s):  
Wei-Li Kuan ◽  
Katherine Stott ◽  
Xiaoling He ◽  
Tobias C. Wood ◽  
Sujeong Yang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Brain Regions ◽  
Neuronal Populations ◽  
Novel Approach ◽  
Quaternary Structures ◽  
Cellular Pathology ◽  
First Time ◽  
The Brain ◽  
Delivery Approach

AbstractParkinson’s disease (PD) is an α-synucleinopathy characterized by the progressive loss of specific neuronal populations. Here, we develop a novel approach to transvascularly deliver proteins of complex quaternary structures, including α-synuclein preformed fibrils (pff). We show that a single systemic administration of α-synuclein pff triggers pathological transformation of endogenous α-synuclein in non-transgenic rats, which leads to neurodegeneration in discrete brain regions. Specifically, pff-exposed animals displayed a progressive deterioration in gastrointestinal and olfactory functions, which corresponded with the presence of cellular pathology in the central and enteric nervous systems. The α-synuclein pathology generated was both time dependent and region specific. Interestingly, the most significant neuropathological changes were observed in those brain regions affected in the early stages of PD. Our data therefore demonstrate for the first time that a single, transvascular administration of α-synuclein pff can lead to selective regional neuropathology resembling the premotor stage of idiopathic PD. Furthermore, this novel delivery approach could also be used to deliver a range of other pathogenic, as well as therapeutic, protein cargos transvascularly to the brain.

scholarly journals Pronounced α-synuclein pathology in a seeding-based mouse model is not sufficient to induce mitochondrial respiration deficits in the striatum and amygdala

2020 ◽  
Author(s):  
Johannes Burtscher ◽  
Jean-Christophe Copin ◽  
Carmen Sandi ◽  
Hilal A. Lashuel
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Respiration ◽  
Early Stage ◽  
Relevant Literature ◽  
Brain Regions ◽  
Substantia Nigra Pars Compacta ◽  
Ros Generation

AbstractIncreasing evidence suggests that crosstalk between α-synuclein pathology formation and mitochondrial dysfunctions plays a central role in the pathogenesis of Parkinson’s disease and related synucleinopathies. While mitochondrial dysfunction is a well-studied phenomenon in the substantia nigra, which is selectively vulnerable in Parkinson’s disease and some models thereof, less information is available in other brain regions that are also affected by synuclein pathology.Therefore, we sought to test the hypothesis that early α-synuclein pathology causes mitochondrial dysfunction, and that this effect might be exacerbated in conditions of increased vulnerability of affected brain regions, such as the amygdala.We combined a model of intracerebral α-synuclein pathology seeding with chronic glucocorticoid treatment modelling non-motor symptoms of Parkinson’s disease and affecting amygdala physiology. We measured mitochondrial respiration, ROS generation and protein abundance as well as α-synuclein pathology in male mice.Chronic corticosterone administration induced mitochondrial hyperactivity in the amygdala. Although injection of α-synuclein preformed fibrils into the striatum resulted in pronounced α-synuclein pathology in both striatum and amygdala, mitochondrial respiration in these brain regions was altered in neither chronic corticosterone nor control conditions.Our results suggest that early stage α-synuclein pathology does not influence mitochondrial respiration in the striatum and amygdala, even in corticosterone-induced respirational hyperactivity. We discuss our findings in light of relevant literature, warn of a potential publication bias and encourage scientist to report their negative results in the frame of this model.Significance statementWe provide evidence that early stage synucleinopathy by itself or in combination with exogenous corticosterone induced amygdala hyperactivity did not compromise mitochondrial respiration in the striatum and amygdala in one of the most commonly used models of synucleinopathies. These results may explain, why this model in the hands of many research groups does not elicit pronounced Parkinson’s disease like symptoms in the absence of mitochondrial dysfunction in brain regions strongly affected by synuclein pathology and involved in non-motor (amygdala) and motor (striatum) symptoms. Our findings call for rigorous investigation of the short- and long-term effects of α-synuclein pathology on mitochondrial function/dysfunction in this model, in particular in brain regions strongly affected by neurodegeneration such as the substantia nigra pars compacta.

scholarly journals Lafora and Trétiakoff: the naming of the inclusion bodies discovered by Lewy

2017 ◽  
Vol 75 (10) ◽  
pp. 751-753 ◽  
Author(s):  
Eliasz Engelhardt
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Inclusion Bodies ◽  
Lewy Bodies ◽  
Brain Nuclei ◽  
Paralysis Agitans ◽  
One Year ◽  
First Time

ABSTRACT Fritz Heinrich Jakob Lewy described, for the first time, in 1912, novel peculiar inclusions in neurons of certain brain nuclei in patients with Paralysis agitans, and compared his finding to the amyloid bodies described by Lafora one year before. Gonzalo Rodriguez Lafora studied one patient with Paralysis agitans, in 1913, and recognized, described, and depicted structures identical to those previously reported by Lewy. He was the first to acknowledge Lewy's finding, and also the first to name such inclusions after the discoverer – cuerpos intracelulares de Lewy (Lewy bodies). Konstantin Nikolaevich Trétiakoff named the inclusions he found in neurons of the substantia nigra of patients with Parkinson's disease as corps de Lewy (Lewy bodies), in 1919. Trétiakoff has unanimously received the credit for the eponym. However, Lafora's earlier description should make him deserving of the authorship of the eponym.

scholarly journals The Link between Gaucher Disease and Parkinson’s Disease Sheds Light on Old and Novel Disorders of Sphingolipid Metabolism

2019 ◽  
Vol 20 (13) ◽  
pp. 3304 ◽  
Author(s):  
Rossella Indellicato ◽  
Marco Trinchera
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gaucher Disease ◽  
Lysosomal Storage Diseases ◽  
Krabbe Disease ◽  
Sphingolipid Metabolism ◽  
Lysosomal Storage ◽  
Lysosomal Hydrolases ◽  
Inborn Errors ◽  
Vesicle Traffic

Sphingolipid metabolism starts with the biosynthesis of ceramide, a bioactive lipid and the backbone for the biosynthesis of complex sphingolipids such as sphingomyelin and glycosphingolipids. These are degraded back to ceramide and then to sphingosine, which enters the ceramide–sphingosine-1-phosphate signaling pathway or is further degraded. Several enzymes with multiple catalytic properties and subcellular localizations are thus involved in such metabolism. Hereditary defects of lysosomal hydrolases have been known for several years to be the cause of lysosomal storage diseases such as gangliosidoses, Gaucher disease, Niemann–Pick disease, Krabbe disease, Fabry disease, and Farber disease. More recently, many other inborn errors of sphingolipid metabolism have been recognized, involving enzymes responsible for the biosynthesis of ceramide, sphingomyelin, and glycosphingolipids. Concurrently, epidemiologic and biochemical evidence has established a link between Gaucher disease and Parkinson’s disease, showing that glucocerebrosidase variants predispose individuals to α-synuclein accumulation and neurodegeneration even in the heterozygous status. This appears to be due not only to lysosomal overload of non-degraded glucosylceramide, but to the derangement of vesicle traffic and autophagy, including mitochondrial autophagy, triggered by both sphingolipid intermediates and misfolded proteins. In this review, old and novel disorders of sphingolipid metabolism, in particular those of ganglioside biosynthesis, are evaluated in light of recent investigations of the link between Gaucher disease and Parkinson’s disease, with the aim of better understanding their pathogenic mechanisms and addressing new potential therapeutic strategies.

scholarly journals Complex Network-Driven View of Genomic Mechanisms Underlying Parkinson’s Disease: Analyses in Dorsal Motor Vagal Nucleus, Locus Coeruleus, and Substantia Nigra

2014 ◽  
Vol 2014 ◽  
pp. 1-16 ◽  
Author(s):  
Beatriz Raposo Corradini ◽  
Priscila Iamashita ◽  
Edilaine Tampellini ◽  
José Marcelo Farfel ◽  
Lea Tenenholz Grinberg ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Locus Coeruleus ◽  
Molecular Mechanisms ◽  
Brain Regions ◽  
Substantia Nigra Pars Compacta ◽  
Gene Sets ◽  
Coexpression Networks ◽  
Ageing Brain

Parkinson’s disease (PD)—classically characterized by severe loss of dopaminergic neurons in the substantia nigra pars compacta—has a caudal-rostral progression, beginning in the dorsal motor vagal nucleus and, in a less extent, in the olfactory system, progressing to the midbrain and eventually to the basal forebrain and the neocortex. About 90% of the cases are idiopathic. To study the molecular mechanisms involved in idiopathic PD we conducted a comparative study of transcriptional interaction networks in the dorsal motor vagal nucleus (VA), locus coeruleus (LC), and substantia nigra (SN) of idiopathic PD in Braak stages 4-5 (PD) and disease-free controls (CT) using postmortem samples. Gene coexpression networks (GCNs) for each brain region (patients and controls) were obtained to identify highly connected relevant genes (hubs) and densely interconnected gene sets (modules). GCN analyses showed differences in topology and module composition between CT and PD networks for each anatomic region. In CT networks, VA, LC, and SN hub modules are predominantly associated with neuroprotection and homeostasis in the ageing brain, whereas in the patient’s group, for the three brain regions, hub modules are mostly related to stress response and neuron survival/degeneration mechanisms.

scholarly journals Regional Metal Concentrations in Parkinson's Disease, Other Chronic Neurological Diseases, and Control Brains

1989 ◽  
Vol 16 (3) ◽  
pp. 310-314 ◽  
Author(s):  
Ryan J. Uitti ◽  
A.H. Rajput ◽  
B. Rozdilsky ◽  
M. Bickis ◽  
T. Wollin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Caudate Nucleus ◽  
Neurological Diseases ◽  
Neurofibrillary Tangle ◽  
Atomic Emission ◽  
Brain Regions ◽  
Metal Concentrations ◽  
And Control

ABSTRACT:Metal deficiency or toxicity states have been recognized as a cause of several neurological disorders and are suspected in others. We analyzed four brain regions (frontal cortex, caudate nucleus, substantia nigra, and cerebellum) in 36 human brains for concentrations of 24 metals (Ag, Al, As, B, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Pb, Mg, Mn, Mo, Na, Ni, P, Se, Ti, V, W, Zn). Regional metal concentrations, measured using atomic absorption and atomic emission spectroscopy, were compared between 9 Parkinson's disease (PD) brains, 15 brains from patients with other chronic neurological diseases, and 12 control brains. No significant metal concentration differences were noted between brains from PD and other chronic neurologic disease. However, parkinsonian brains (PD and parkinsonism secondary to neurofibrillary tangle disease) showed lower concentrations of magnesium in the caudate nucleus and copper in the substantia nigra than control brains. These findings may represent an etiologically important clue to parkinsonism.

scholarly journals The Emerging Role of the Lysosome in Parkinson’s Disease

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2399
Author(s):  
Alba Navarro-Romero ◽  
Marta Montpeyó ◽  
Marta Martinez-Vicente
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Risk ◽  
Lysosomal Storage Diseases ◽  
Genetic Risk Factors ◽  
Brain Regions ◽  
Lysosomal Storage ◽  
Lysosomal Function ◽  
Lysosomal Dysfunction

Lysosomal function has a central role in maintaining neuronal homeostasis, and, accordingly, lysosomal dysfunction has been linked to neurodegeneration and particularly to Parkinson’s disease (PD). Lysosomes are the converging step where the substrates delivered by autophagy and endocytosis are degraded in order to recycle their primary components to rebuild new macromolecules. Genetic studies have revealed the important link between the lysosomal function and PD; several of the autosomal dominant and recessive genes associated with PD as well as several genetic risk factors encode for lysosomal, autophagic, and endosomal proteins. Mutations in these PD-associated genes can cause lysosomal dysfunction, and since α-synuclein degradation is mostly lysosomal-dependent, among other consequences, lysosomal impairment can affect α-synuclein turnover, contributing to increase its intracellular levels and therefore promoting its accumulation and aggregation. Recent studies have also highlighted the bidirectional link between Parkinson’s disease and lysosomal storage diseases (LSD); evidence includes the presence of α-synuclein inclusions in the brain regions of patients with LSD and the identification of several lysosomal genes involved in LSD as genetic risk factors to develop PD.

scholarly journals Epigenetic Study in Parkinson’s Disease: A Pilot Analysis of DNA Methylation in Candidate Genes in Brain

Cells ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 150 ◽  
Author(s):  
Luis Navarro-Sánchez ◽  
Beatriz Águeda-Gómez ◽  
Silvia Aparicio ◽  
Jordi Pérez-Tur
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Dna Methylation ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Brain Regions ◽  
Epigenetic Factors ◽  
Promoter Regions ◽  
Disease Pathogenesis ◽  
Cpg Dinucleotides

Efforts have been made to understand the pathophysiology of Parkinson’s disease (PD). A significant number of studies have focused on genetics, despite the fact that the described pathogenic mutations have been observed only in around 10% of patients; this observation supports the fact that PD is a multifactorial disorder. Lately, differences in miRNA expression, histone modification, and DNA methylation levels have been described, highlighting the importance of epigenetic factors in PD etiology. Taking all this into consideration, we hypothesized that an alteration in the level of methylation in PD-related genes could be related to disease pathogenesis, possibly due to alterations in gene expression. After analysing promoter regions of five PD-related genes in three brain regions by pyrosequencing, we observed some differences in DNA methylation levels (hypo and hypermethylation) in substantia nigra in some CpG dinucleotides that, possibly through an alteration in Sp1 binding, could alter their expression.

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