Alpha synuclein (SNCA) rs7684318 variant contributes to Parkinson’s disease risk by altering transcription factor binding related with Notch and Wnt signaling

2021 ◽  
Vol 750 ◽  
pp. 135802
Author(s):  
Shaik Mohammad Naushad ◽  
Tajamul Hussain ◽  
Salman Alrokayan ◽  
Vijay Kumar Kutala
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcription Factor ◽  
Wnt Signaling ◽  
Disease Risk ◽  
Transcription Factor Binding ◽  
Alpha Synuclein ◽  
Factor Binding

scholarly journals Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk

2018 ◽  
Vol 50 (10) ◽  
pp. 1483-1493 ◽  
Author(s):  
Yakir A. Reshef ◽  
Hilary K. Finucane ◽  
David R. Kelley ◽  
Alexander Gusev ◽  
Dylan Kotliar ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Disease Risk ◽  
Transcription Factor Binding ◽  
Factor Binding ◽  
Polygenic Disease ◽  
Genome Wide

scholarly journals ATF4 regulates neuronal death in models of Parkinson’s Disease

2019 ◽  
Author(s):  
Matthew D. Demmings ◽  
Gillian N. Petroff ◽  
Heather E. Tarnowski-Garner ◽  
Sean P. Cregan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcription Factor ◽  
Neuronal Death ◽  
Target Genes ◽  
Kinase Inhibitor ◽  
Alpha Synuclein ◽  
Dependent Manner ◽  
Dopaminergic Cell ◽  
Cellular Models

AbstractParkinson’s Disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra resulting in severe motor impairments. However, the mechanisms underlying this neuronal loss remain largely unknown. Activating Transcription Factor 4 (ATF4), a key mediator of the Integrated Stress Response (ISR), is a transcription factor that during prolonged activation can induce the expression of pro-apoptotic target genes. Oxidative stress and ER stress have been implicated in PD and these factors are known to activate the ISR. In this study, we have determined, that both PD neurotoxins (MPP+ and 6-OHDA) and α-synuclein aggregation induced by pre-formed human alpha-synuclein fibrils (PFFs) cause sustained upregulation of ATF4 expression in mouse primary cortical and mesencephalic neurons. Furthermore, we demonstrate that PD neurotoxins induce the expression of the pro-apoptotic factors Chop, Trb3 and Puma in an ATF4-dependent manner. Importantly, using neurons derived from ATF4 +/+ and ATF4 -/- mice, we demonstrate that ATF4 promotes neuronal apoptosis and dopaminergic cell loss in cellular models of PD. Finally, we demonstrate that the eIF2α kinase inhibitor C16 suppresses MPP+ and 6-OHDA induced ATF4 activation and protects against PD neurotoxin induced neuronal death. Taken together these results indicate that ATF4 is a key regulator of dopaminergic cell death induced by PD neurotoxins and pathogenic α-synuclein aggregates and highlight the ISR as a potential therapeutic target in PD.

scholarly journals Integration of functional genomics data to uncover cell type-specific pathways affected in Parkinson's disease

2021 ◽  
Author(s):  
Viola Volpato
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Disease Risk ◽  
Late Onset ◽  
Alpha Synuclein ◽  
Biological Information ◽  
Cell Type ◽  
Risk Variants ◽  
Cell Type Specific

Parkinson's disease (PD) is the second most prevalent late-onset neurodegenerative disorder worldwide after Alzheimer's disease for which available drugs only deliver temporary symptomatic relief. Loss of dopaminergic neurons (DaNs) in the substantia nigra and intracellular alpha-synuclein inclusions are the main hallmarks of the disease but the events that cause this degeneration remain uncertain. Despite cell types other than DaNs such as astrocytes, microglia and oligodendrocytes have been recently associated with the pathogenesis of PD, we still lack an in-depth characterisation of PD-affected brain regions at cell-type resolution that could help our understanding of the disease mechanisms. Nevertheless, publicly available large-scale brain-specific genomic, transcriptomic and epigenomic datasets can be further exploited to extract different layers of cell type-specific biological information for the reconstruction of cell type-specific transcriptional regulatory networks. By intersecting disease risk variants within the networks, it may be possible to study the functional role of these risk variants and their combined effects at cell type- and pathway levels, that, in turn, can facilitate the identification of key regulators involved in disease progression, which are often potential therapeutic targets.

scholarly journals Functions of Intracellular Alpha-Synuclein in Microglia: Implications for Parkinson’s Disease Risk

2021 ◽  
Vol 15 ◽  
Author(s):  
Alix Booms ◽  
Gerhard A. Coetzee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Significant Risk ◽  
Physiological Role ◽  
Significant Risk Factor ◽  
Cell Types ◽  
Alpha Synuclein ◽  
Vesicle Formation ◽  
Immune Functions

Alpha-synuclein accumulation in dopaminergic neurons is one of the primary features of Parkinson’s disease (PD). Despite its toxic properties during PD, alpha-synuclein has some important physiological functions. Although the activity of the protein has been extensively studied in neurons, the protein is also expressed in other cell types including immune cells and glia. Genetic studies show that mutations in synuclein alpha (SNCA), the gene that encodes alpha-synuclein, and alterations in its expression levels are a significant risk factor for PD, which likely impact the functions of a broad range of cell types. The consequences of altered SNCA expression in other cell types is beginning to be explored. Microglia, the primary macrophage population in the Central Nervous System (CNS), for example, are affected by variations in alpha-synuclein levels and functions. Studies suggest that deviations of alpha-synuclein’s normal activity influence hematopoiesis, the process that gives rise to microglia, and microglia’s immune functions. Alpha-synuclein levels also dictate the efficiency of SNARE-mediated vesicle formation, which could influence autophagy and cytokine release in microglia. Starting from the time of conception, these effects could impact one’s risk for developing PD. Further studies are needed to determine the physiological role of alpha-synuclein and how the protein is affected during PD in non-neuronal cells such as microglia. In this review we will discuss the known roles of alpha-synuclein in differentiation, immune responses, and vesicle formation, with insights into how abnormal alpha-synuclein expression and activity are linked to altered functions of microglia during PD.

scholarly journals Pooled ChIP-Seq Links Variation in Transcription Factor Binding to Complex Disease Risk

Cell ◽  
2016 ◽  
Vol 165 (3) ◽  
pp. 730-741 ◽  
Author(s):  
Ashley K. Tehranchi ◽  
Marsha Myrthil ◽  
Trevor Martin ◽  
Brian L. Hie ◽  
David Golan ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Complex Disease ◽  
Disease Risk ◽  
Transcription Factor Binding ◽  
Factor Binding

Author response for "Transcription factor binding at immunoglobulin enhancers is linked to somatic hypermutation targeting"

2019 ◽  
Author(s):  
Ravi K. Dinesh ◽  
Benjamin Barnhill ◽  
Anoj Ilanges ◽  
Lizhen Wu ◽  
Daniel A. Michelson ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Somatic Hypermutation ◽  
Transcription Factor Binding ◽  
Author Response ◽  
Factor Binding
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