Genetic basis of Parkinson disease

2010 ◽  
Vol 28 (1) ◽  
pp. E7 ◽  
Author(s):  
Georgia Xiromerisiou ◽  
Efthimios Dardiotis ◽  
Vaïa Tsimourtou ◽  
Persa Maria Kountra ◽  
Konstantinos N. Paterakis ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Molecular Mechanisms ◽  
Autosomal Recessive Inheritance ◽  
Alpha Synuclein ◽  
Collaborative Studies ◽  
Common Genetic Variants ◽  
Cellular Pathways ◽  
Meta Analyses ◽  
Shed Light ◽  
Made In

Over the past few years, considerable progress has been made in understanding the molecular mechanisms of Parkinson disease (PD). Mutations in certain genes are found to cause monogenic forms of the disorder, with autosomal dominant or autosomal recessive inheritance. These genes include alpha-synuclein, parkin, PINK1, DJ-1, LRRK2, and ATP13A2. The monogenic variants are important tools in identifying cellular pathways that shed light on the pathogenesis of this disease. Certain common genetic variants are also likely to modulate the risk of PD. International collaborative studies and meta-analyses have identified common variants as genetic susceptibility risk/protective factors for sporadic PD.

scholarly journals Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 375
Author(s):  
Inês C. Brás ◽  
Tiago F. Outeiro
Keyword(s):  
Molecular Mechanisms ◽  
Brain Regions ◽  
Alpha Synuclein ◽  
Therapeutic Strategies ◽  
Cell Protein ◽  
Protein Assemblies ◽  
Lewy Pathology ◽  
Tremendous Progress ◽  
The Brain ◽  
Made In

The accumulation of misfolded alpha-synuclein (aSyn) throughout the brain, as Lewy pathology, is a phenomenon central to Parkinson’s disease (PD) pathogenesis. The stereotypical distribution and evolution of the pathology during disease is often attributed to the cell-to-cell transmission of aSyn between interconnected brain regions. The spreading of conformationally distinct aSyn protein assemblies, commonly referred as strains, is thought to result in a variety of clinically and pathologically heterogenous diseases known as synucleinopathies. Although tremendous progress has been made in the field, the mechanisms involved in the transfer of these assemblies between interconnected neural networks and their role in driving PD progression are still unclear. Here, we present an update of the relevant discoveries supporting or challenging the prion-like spreading hypothesis. We also discuss the importance of aSyn strains in pathology progression and the various putative molecular mechanisms involved in cell-to-cell protein release. Understanding the pathways underlying aSyn propagation will contribute to determining the etiology of PD and related synucleinopathies but also assist in the development of new therapeutic strategies.

scholarly journals Glucocerebrosidase and Parkinson Disease: Molecular, Clinical, and Therapeutic Implications

2018 ◽  
Vol 24 (5) ◽  
pp. 540-559 ◽  
Author(s):  
Roberta Balestrino ◽  
Anthony H. V. Schapira
Keyword(s):  
Parkinson Disease ◽  
Molecular Mechanisms ◽  
Alpha Synuclein ◽  
Substrate Reduction Therapy ◽  
Lysosomal Disorder ◽  
Therapeutic Implications ◽  
Substrate Reduction ◽  
Gba Gene ◽  
Alpha Synuclein Aggregation ◽  
Non Motor Symptoms

Parkinson disease (PD) is a complex neurodegenerative disease characterised by multiple motor and non-motor symptoms. In the last 20 years, more than 20 genes have been identified as causes of parkinsonism. Following the observation of higher risk of PD in patients affected by Gaucher disease, a lysosomal disorder caused by mutations in the glucocerebrosidase (GBA) gene, it was discovered that mutations in this gene constitute the single largest risk factor for development of idiopathic PD. Patients with PD and GBA mutations are clinically indistinguishable from patients with idiopathic PD, although some characteristics emerge depending on the specific mutation, such as slightly earlier onset. The molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are multiple and not yet fully elucidated, they include alpha-synuclein aggregation, lysosomal-autophagy dysfunction and endoplasmic reticulum stress. Moreover, dysfunction of glucocerebrosidase has also been demonstrated in non-GBA PD, suggesting its interaction with other pathogenic mechanisms. Therefore, GBA enzyme function represents an interesting pharmacological target for PD. Cell and animal models suggest that increasing GBA enzyme activity can reduce alpha-synuclein levels. Clinical trials of ambroxol, a glucocerebrosidase chaperone, are currently ongoing in PD and PD dementia, as is a trial of substrate reduction therapy. The aim of this review is to summarise the main features of GBA-PD and discuss the implications of glucocerebrosidase modulation on PD pathogenesis.

Central nervous system physiology in anaesthetic practice

2017 ◽  
Author(s):  
Ram Adapa ◽  
Anthony Absalom
Keyword(s):  
Molecular Mechanisms ◽  
Clinical Care ◽  
Therapeutic Index ◽  
Anaesthetic Agents ◽  
Positron Emission ◽  
Explicit Recall ◽  
System Physiology ◽  
Shed Light ◽  
Neuroimaging Techniques ◽  
Made In

How and where consciousness is generated and maintained remains an unsolved scientific mystery, and this has impeded progress in understanding anaesthesia. In recent years, however, significant progress has been made in understanding the neurobiology of anaesthetic-induced loss of consciousness. This has been made possible by advances in molecular biology techniques, which have helped shed light on the molecular mechanisms of action of the anaesthetic agents. In parallel, the development of neuroimaging techniques, such as functional magnetic resonance imaging and positron emission tomography, has also provided an enormous impetus. These techniques are providing new insights into the neural correlates of consciousness, and new insights into the alterations in neurophysiology associated with impaired consciousness caused by sleep, sedation, and anaesthesia. The information being gained from these studies on the neurobiology of impairments of attention, awareness, and memory will hopefully eventually not only lead to improvements in our understanding of consciousness and anaesthesia, but also to better clinical care. Understanding of memory functions during sedation and anaesthesia may, for example, lead to better strategies for preventing awareness with subsequent explicit recall of intraoperative events. Further, a better understanding of the neurobiology of anaesthetic-induced unconsciousness may inform future development of better anaesthetic agents, with a broader therapeutic index, and fewer unwanted effects.

scholarly journals Common molecular mechanisms underlie the transfer of alpha-synuclein, Tau and huntingtin and modulate spontaneous activity in neuronal cells

2021 ◽  
Author(s):  
Ines Caldeira Bras ◽  
Mohammad Hossein Khani ◽  
Eftychia Vasili ◽  
Wiebke Mobius ◽  
Dietmar Riedel ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neuronal Activity ◽  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Neuronal Cells ◽  
Alpha Synuclein ◽  
Free Form ◽  
Polyglutamine Expansion ◽  
Associated Proteins ◽  
Cellular Pathways

The misfolding and accumulation of disease-related proteins are common hallmarks among several neurodegenerative diseases. Alpha-synuclein (aSyn), Tau and huntingtin (wild-type and mutant, 25QHtt and 103QHtt, respectively) were recently shown to be transferred from cell-to-cell through different cellular pathways, thereby contributing to disease progression and neurodegeneration. However, the relative contribution of each of these mechanisms towards the spreading of these different proteins and the overall effect on neuronal function is still unclear. To address this, we exploited different cell-based systems to conduct a systematic comparison of the mechanisms of release of aSyn, Tau and Htt, and evaluated the effects of each protein upon internalization in microglial, astrocytic, and neuronal cells. In the models used, we demonstrate that 25QHtt, aSyn and Tau are released to the extracellular space at higher levels than 103QHtt, and their release can be further augmented with the co-expression of USP19. Furthermore, cortical neurons treated with recombinant monomeric 43QHtt exhibited alterations in neuronal activity that correlated with the toxicity of the polyglutamine expansion. Tau internalization resulted in an increase in neuronal activity, in contrast to slight effects observed with aSyn. Interestingly, all these disease-associated proteins were present at higher levels in ectosomes than in exosomes. The internalization of both types of extracellular vesicles (EVs) by microglial or astrocytic cells elicited the production of pro-inflammatory cytokines and promoted an increase in autophagy markers. Additionally, the uptake of the EVs modulated neuronal activity in cortical neurons. Overall, our systematic study demonstrates the release of neurodegenerative disease-associated proteins through similar cellular pathways. Furthermore, it emphasizes that protein release, both in a free form or in EVs, might contribute to a variety of detrimental effects in receiving cells and to progression of pathology, suggesting they may be exploited as valid targets for therapeutic intervention in different neurodegenerative diseases.

scholarly journals Integrated multi-omics analysis reveals common and distinct dysregulated pathways for genetic subtypes of Frontotemporal Dementia

2020 ◽  
Author(s):  
Kevin Menden ◽  
Margherita Francescatto ◽  
Tenzin Nyima ◽  
Cornelis Blauwendraat ◽  
Ashutosh Dhingra ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Molecular Mechanisms ◽  
Phase 1 ◽  
Neuronal Cell ◽  
Omics Data ◽  
Rna Seq ◽  
Data Resource ◽  
Cellular Models ◽  
Cellular Pathways ◽  
Shed Light

AbstractUnderstanding the molecular mechanisms underlying frontotemporal dementia (FTD) is essential for the development of successful therapies. Here, we present Phase 1 of a multi-omics, multi-model data resource for FTD research which will allows in-depth molecular research into these mechanisms. We have integrated and analysed data from the frontal lobe of FTD patients with mutations in MAPT, GRN and C9orf72 and detected common and distinct dysregulated cellular pathways. Our results highlight that excitatory neurons are the most vulnerable neuronal cell type and that vascular aberrations are a common hallmark in FTD. Via integration of multi-omics data, we detected several transcription factors and pathways which regulate the strong neuroinflammation observed in FTD-GRN. Finally, using small RNA-seq data and verification experiments in cellular models, we identified several up-regulated miRNAs that inhibit cellular trafficking pathways in FTD and lead to microglial activation. In this work we shed light on novel mechanistic and pathophysiological hallmarks of FTD. In addition, we believe that this comprehensive, multi-omics data resource will further mechanistic FTD research by the community.

scholarly journals Integrated multi-omics analysis reveals common and distinct dysregulated pathways for genetic subtypes of Frontotemporal Dementia

2021 ◽  
Author(s):  
Kevin Menden ◽  
Margherita Francescatto ◽  
Tenzin Niyma ◽  
Cornelis Blauwendraat ◽  
Ashutosh Dhingra ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Molecular Mechanisms ◽  
Neuronal Cell ◽  
Rna Seq ◽  
Data Resource ◽  
Cellular Models ◽  
Patient Groups ◽  
Cellular Pathways ◽  
Human Brains ◽  
Shed Light

Abstract Understanding the molecular mechanisms underlying frontotemporal dementia (FTD) is essential for the development of successful therapies. Here we integrated transcriptomic and epigenomic analyses of postmortem human brains of FTD patients with mutations in MAPT, GRN and C9orf72 and detected common and distinct dysregulated cellular pathways between patient groups. Our results highlight that excitatory neurons are the most vulnerable neuronal cell type and that vascular aberrations are a common hallmark in FTD. Via integration of multi-omics data, we detected several transcription factors and pathways which regulate the strong neuroinflammation observed in FTD-GRN. Small RNA-seq data and verification experiments in cellular models identified up-regulated miRNAs that inhibit cellular trafficking pathways in FTD and lead to microglial activation. These findings shed light on novel mechanistic and pathophysiological hallmarks of FTD. The data represent the 1st phase of a multi-omics, multi-model data resource for FTD research which allows in-depth molecular research into disease mechanisms that will further mechanistic FTD research.

The Role of the Endothelium in Premature Atherosclerosis: Molecular Mechanisms

2020 ◽  
Vol 27 (7) ◽  
pp. 1041-1051 ◽  
Author(s):  
Michael Spartalis ◽  
Eleftherios Spartalis ◽  
Antonios Athanasiou ◽  
Stavroula A. Paschou ◽  
Christos Kontogiannis ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Low Density Lipoprotein ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Number Of Genes ◽  
Causes Of Mortality ◽  
Artery Disease ◽  
Genetic And Environmental Factors ◽  
Made In

Atherosclerotic disease is still one of the leading causes of mortality. Atherosclerosis is a complex progressive and systematic artery disease that involves the intima of the large and middle artery vessels. The inflammation has a key role in the pathophysiological process of the disease and the infiltration of the intima from monocytes, macrophages and T-lymphocytes combined with endothelial dysfunction and accumulated oxidized low-density lipoprotein (LDL) are the main findings of atherogenesis. The development of atherosclerosis involves multiple genetic and environmental factors. Although a large number of genes, genetic polymorphisms, and susceptible loci have been identified in chromosomal regions associated with atherosclerosis, it is the epigenetic process that regulates the chromosomal organization and genetic expression that plays a critical role in the pathogenesis of atherosclerosis. Despite the positive progress made in understanding the pathogenesis of atherosclerosis, the knowledge about the disease remains scarce.

Molecular Mechanisms of Complement System Proteins and Matrix Metalloproteinases in the Pathogenesis of Age-Related Macular Degeneration

2019 ◽  
Vol 19 (10) ◽  
pp. 705-718 ◽  
Author(s):  
Naima Mansoor ◽  
Fazli Wahid ◽  
Maleeha Azam ◽  
Khadim Shah ◽  
Anneke I. den Hollander ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Macular Degeneration ◽  
Complement System ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Age Related Macular Degeneration ◽  
Genetic Changes ◽  
Complement System Proteins ◽  
Age Related ◽  
Common Genetic Variants

: Age-related macular degeneration (AMD) is an eye disorder affecting predominantly the older people above the age of 50 years in which the macular region of the retina deteriorates, resulting in the loss of central vision. The key factors associated with the pathogenesis of AMD are age, smoking, dietary, and genetic risk factors. There are few associated and plausible genes involved in AMD pathogenesis. Common genetic variants (with a minor allele frequency of >5% in the population) near the complement genes explain 40–60% of the heritability of AMD. The complement system is a group of proteins that work together to destroy foreign invaders, trigger inflammation, and remove debris from cells and tissues. Genetic changes in and around several complement system genes, including the CFH, contribute to the formation of drusen and progression of AMD. Similarly, Matrix metalloproteinases (MMPs) that are normally involved in tissue remodeling also play a critical role in the pathogenesis of AMD. MMPs are involved in the degradation of cell debris and lipid deposits beneath retina but with age their functions get affected and result in the drusen formation, succeeding to macular degeneration. In this review, AMD pathology, existing knowledge about the normal and pathological role of complement system proteins and MMPs in the eye is reviewed. The scattered data of complement system proteins, MMPs, drusenogenesis, and lipofusogenesis have been gathered and discussed in detail. This might add new dimensions to the understanding of molecular mechanisms of AMD pathophysiology and might help in finding new therapeutic options for AMD.

scholarly journals Direct current stimulation enhances neuronal alpha-synuclein degradation in vitro

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Gessica Sala ◽  
Tommaso Bocci ◽  
Valentina Borzì ◽  
Marta Parazzini ◽  
Alberto Priori ◽  
...  
Keyword(s):  
Direct Current ◽  
Molecular Mechanisms ◽  
Neuroblastoma Cell ◽  
Alpha Synuclein ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Direct Current Stimulation ◽  
Gene And Protein Expression ◽  
Autophagic Degradation ◽  
On Line

AbstractDespite transcranial Direct Current Stimulation (DCS) is currently proposed as a symptomatic treatment in Parkinson’s disease, the intracellular and molecular mechanisms elicited by this technique are still unknown, and its disease-modifying potential unexplored. Aim of this study was to elucidate the on-line and off-line effects of DCS on the expression, aggregation and degradation of alpha-synuclein (asyn) in a human neuroblastoma cell line under basal conditions and in presence of pharmachologically-induced increased asyn levels. Following DCS, gene and protein expression of asyn and its main autophagic catabolic pathways were assessed by real-time PCR and Western blot, extracellular asyn levels by Dot blot. We found that, under standard conditions, DCS increased monomeric and reduced oligomeric asyn forms, with a concomitant down-regulation of both macroautophagy and chaperone-mediated autophagy. Differently, in presence of rotenone-induced increased asyn, DCS efficiently counteracted asyn accumulation, not acting on its gene transcription, but potentiating its degradation. DCS also reduced intracellular and extracellular asyn levels, increased following lysosomal inhibition, independently from autophagic degradation, suggesting that other mechanisms are also involved. Collectively, these findings suggest that DCS exerts on-line and off-line effects on the expression, aggregation and autophagic degradation of asyn, indicating a till unknown neuroprotective role of tDCS.

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