scholarly journals Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease

2021 ◽  
Vol 22 (12) ◽  
pp. 6277
Author(s):  
Joanna A. Motyl ◽  
Joanna B. Strosznajder ◽  
Agnieszka Wencel ◽  
Robert P. Strosznajder
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Fate ◽  
Neuronal Death ◽  
Neurological Diseases ◽  
Alpha Synuclein ◽  
Lipid Mediator ◽  
Cell Defense ◽  
Promising Therapeutic Approach ◽  
S1p Receptor

Molecular studies have provided increasing evidence that Parkinson’s disease (PD) is a protein conformational disease, where the spread of alpha-synuclein (ASN) pathology along the neuraxis correlates with clinical disease outcome. Pathogenic forms of ASN evoke oxidative stress (OS), neuroinflammation, and protein alterations in neighboring cells, thereby intensifying ASN toxicity, neurodegeneration, and neuronal death. A number of evidence suggest that homeostasis between bioactive sphingolipids with opposing function—e.g., sphingosine-1-phosphate (S1P) and ceramide—is essential in pro-survival signaling and cell defense against OS. In contrast, imbalance of the “sphingolipid biostat” favoring pro-oxidative/pro-apoptotic ceramide-mediated changes have been indicated in PD and other neurodegenerative disorders. Therefore, we focused on the role of sphingolipid alterations in ASN burden, as well as in a vast range of its neurotoxic effects. Sphingolipid homeostasis is principally directed by sphingosine kinases (SphKs), which synthesize S1P—a potent lipid mediator regulating cell fate and inflammatory response—making SphK/S1P signaling an essential pharmacological target. A growing number of studies have shown that S1P receptor modulators, and agonists are promising protectants in several neurological diseases. This review demonstrates the relationship between ASN toxicity and alteration of SphK-dependent S1P signaling in OS, neuroinflammation, and neuronal death. Moreover, we discuss the S1P receptor-mediated pathways as a novel promising therapeutic approach in PD.

scholarly journals TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease

2017 ◽  
Vol 114 (40) ◽  
pp. 10773-10778 ◽  
Author(s):  
Seong Su Kang ◽  
Zhentao Zhang ◽  
Xia Liu ◽  
Fredric P. Manfredsson ◽  
Matthew J. Benskey ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Death ◽  
Kinase Domain ◽  
Alpha Synuclein ◽  
Mao B ◽  
Protein Levels ◽  
Trkb Receptors ◽  
Alpha Synuclein Aggregation ◽  
Neurotrophic Signaling

BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson’s disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase. Interestingly, α-Syn represses TrkB lipid raft distribution, decreases its internalization, and reduces its axonal trafficking. Moreover, α-Syn also reduces TrkB protein levels via up-regulation of TrkB ubiquitination. Remarkably, dopamine’s metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL) stimulates the interaction between α-Syn and TrkB. Accordingly, MAO-B inhibitor rasagiline disrupts α-Syn/TrkB complex and rescues TrkB neurotrophic signaling, preventing α-Syn–induced dopaminergic neuronal death and restoring motor functions. Hence, our findings demonstrate a noble pathological role of α-Syn in antagonizing neurotrophic signaling, providing a molecular mechanism that accounts for its neurotoxicity in PD.

scholarly journals Alpha-Synuclein Oligomers Interact with Metal Ions to Induce Oxidative Stress and Neuronal Death in Parkinson's Disease

2016 ◽  
Vol 24 (7) ◽  
pp. 376-391 ◽  
Author(s):  
Emma Deas ◽  
Nunilo Cremades ◽  
Plamena R. Angelova ◽  
Marthe H.R. Ludtmann ◽  
Zhi Yao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Metal Ions ◽  
Neuronal Death ◽  
Alpha Synuclein

scholarly journals Expression of the Parkinson’s Disease-Associated Gene Alpha-Synuclein is Regulated by the Neuronal Cell Fate Determinant TRIM32

2016 ◽  
Vol 54 (6) ◽  
pp. 4257-4270 ◽  
Author(s):  
Maria Angeliki S. Pavlou ◽  
Nicoló Colombo ◽  
Sandra Fuertes-Alvarez ◽  
Sarah Nicklas ◽  
Laura Gonzalez Cano ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Fate ◽  
Neuronal Cell ◽  
Alpha Synuclein ◽  
Cell Fate Determinant

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 PARK Genes Link Mitochondrial Dysfunction and Alpha-Synuclein Pathology in Sporadic Parkinson’s Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Wen Li ◽  
YuHong Fu ◽  
Glenda M. Halliday ◽  
Carolyn M. Sue
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorder ◽  
Alpha Synuclein ◽  
Lewy Pathology ◽  
Age Related ◽  
Promising Therapeutic Approach ◽  
Park Genes

Parkinson’s disease (PD) is an age-related neurodegenerative disorder affecting millions of people worldwide. The disease is characterized by the progressive loss of dopaminergic neurons and spread of Lewy pathology (α-synuclein aggregates) in the brain but the pathogenesis remains elusive. PD presents substantial clinical and genetic variability. Although its complex etiology and pathogenesis has hampered the breakthrough in targeting disease modification, recent genetic tools advanced our approaches. As such, mitochondrial dysfunction has been identified as a major pathogenic hub for both familial and sporadic PD. In this review, we summarize the effect of mutations in 11 PARK genes (SNCA, PRKN, PINK1, DJ-1, LRRK2, ATP13A2, PLA2G6, FBXO7, VPS35, CHCHD2, and VPS13C) on mitochondrial function as well as their relevance in the formation of Lewy pathology. Overall, these genes play key roles in mitochondrial homeostatic control (biogenesis and mitophagy) and functions (e.g., energy production and oxidative stress), which may crosstalk with the autophagy pathway, induce proinflammatory immune responses, and increase oxidative stress that facilitate the aggregation of α-synuclein. Thus, rectifying mitochondrial dysregulation represents a promising therapeutic approach for neuroprotection in PD.

scholarly journals Alpha-Synuclein is a Target of Fic-mediated Adenylylation/AMPylation: Implications for Parkinson’s Disease

2019 ◽  
Author(s):  
Anwesha Sanyal ◽  
Sayan Dutta ◽  
Aswathy Chandran ◽  
Antonius Koller ◽  
Ali Camara ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Er Stress ◽  
Cell Fate ◽  
Alpha Synuclein ◽  
Misfolded Proteins ◽  
List Type ◽  
Post Translational Modification ◽  
Presynaptic Protein

ABSTRACTDuring disease, cells experience various stresses that manifest as an accumulation of misfolded proteins and eventually lead to cell death. To combat this stress, cells activate a pathway called UPR (Unfolded Protein Response) that functions to maintain ER (endoplasmic reticulum) homeostasis and determines cell fate. We recently reported a hitherto unknown mechanism of regulating ER stress via a novel post-translational modification (PTM) called Fic-mediated Adenylylation/AMPylation. Specifically, we showed that the human Fic (filamentation induced by cAMP) protein, HYPE/FicD, catalyzes the addition of an AMP (adenosine monophosphate) to the ER chaperone, BiP, to alter the cell’s UPR-mediated response to misfolded proteins. Here, we report that we have now identified a second target for HYPE - alpha-Synuclein (αSyn), a presynaptic protein involved in Parkinson’s disease (PD). Aggregated αSyn has been shown to induce ER stress and elicit neurotoxicity in PD models. We show that HYPE adenylylates αSyn and reduces phenotypes associated with αSyn aggregation in vitro, suggesting a possible mechanism by which cells cope with αSyn toxicity.HIGHLIGHTSAggregated forms of the presynaptic protein αSyn cause neurotoxicity and induce ER stress in cellular and animal models of Parkinson’s disease.We have identified αSyn as a novel target for the human Fic protein, HYPE, a key regulator of ER homeostasis.HYPE adenylylates αSyn and reduces the aggregation of recombinant αSynFic-mediated adenylylation/AMPylation is a possible mechanism by which cells cope with αSyn toxicity.Graphic Abstract

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