Membrane Interactions of Oligomeric Alpha-Synuclein: Potential Role in Parkinsons Disease

2010 ◽  
Vol 11 (5) ◽  
pp. 334-342 ◽  
Author(s):  
Bart D. van Rooijen ◽  
Mireille M.A.E. Claessens ◽  
Vinod Subramaniam
Keyword(s):  
Potential Role ◽  
Alpha Synuclein ◽  
Membrane Interactions ◽  
Parkinsons Disease

Potential role of protein stabilizers in amelioration of Parkinson's disease and associated effects in transgenic Caenorhabditis elegans model expressing alpha-synuclein

RSC Advances ◽  
2015 ◽  
Vol 5 (95) ◽  
pp. 77706-77715 ◽  
Author(s):  
Supinder Kaur ◽  
Aamir Nazir
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Caenorhabditis Elegans ◽  
Potential Role ◽  
Alpha Synuclein ◽  
C Elegans

Studies employing transgenicC. elegansmodel show that trehalose, a protein stabilizer, alleviates manifestations associated with Parkinson's diseaseviaits inherent activity and through induction of autophagic machinery.

scholarly journals The SNCA-Rep1 Polymorphic Locus: Association with the Risk of Parkinson’s Disease and SNCA Gene Methylation

Acta Naturae ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 105-110 ◽  
Author(s):  
E. V. Iakovenko ◽  
N. Yu. Abramycheva ◽  
E. Yu. Fedotova ◽  
S. N. Illarioshkin
Keyword(s):  
Molecular Marker ◽  
Polymorphic Locus ◽  
Alpha Synuclein ◽  
Gene Methylation ◽  
Allelic Variants ◽  
Parkinsons Disease ◽  
Cpg Sites ◽  
Snca Gene ◽  
Intron 1 ◽  
Significant Region

Neurodegeneration in Parkinsons disease is characterized by the accumulation of alpha-synuclein, aprotein encoded by theSNCAgene, in neurons. In addition to mutations, many polymorphisms have been identified in this gene, and one of theseis a dinucleotide microsatellite:SNCA-Rep1.The mechanisms by which specific configurations ofSNCA-Rep1 may contribute to the development of this disease have yet to be clarified. Inour study, a relationship between longSNCA-Rep1 alleles and Parkinsons was confirmed in the Russian population. Long allelic variants ofSNCA-Rep1 were shown to be associated with the hypomethylation of the CpG-sites in intron 1 of theSNCAgene. Long variants ofSNCA-Rep1 are supposed to exert their effect through the hypomethylation of atranscriptionally significant region of this gene. Hypomethylation is usually associated with increased expression, which, in turn, contributes to alpha-synuclein accumulation in neuronal cytoplasm, with the latter being the main molecular marker of Parkinsons disease. Further studies are needed to establish a relationship between our finding andSNCAgene expression.

scholarly journals A COMPLEMENTARY APPROACH ON OLFACTORY DYSFUNCTION IN PARKINSONS DISEASE- RETROSPECTIVE OBSERVATIONAL STUDY

2020 ◽  
pp. 25-32
Author(s):  
Nair Sandeep Damodharan ◽  
Vijayagopal Sunil Kumar ◽  
Przuntek Horst ◽  
Webering Nadine ◽  
Hegelmaier Tobias
Keyword(s):  
Neuronal Degeneration ◽  
Alpha Synuclein ◽  
Olfactory Dysfunction ◽  
Motor Symptom ◽  
Test Results ◽  
Parkinsons Disease ◽  
Complementary Approach ◽  
Smell Test ◽  
Significant Difference ◽  
Before And After

Olfactory dysfunction is a frequent non-motor symptom of Parkinson’s disease (PD) that involves deficits in odour detection, discrimination, and identification. Hyposmia may be related to neuronal degeneration with deposition of alpha-synuclein in primary olfactory areas as a very early component of the pathology of PD. Olfactory dysfunction also known as Gandhajnana or Gandhanaasha in Ayurveda is a result of improper functioning of different Vatasdue to either degeneration of Dhathus (Tissues) or obstruction in the normal movement of Vata. We analysed the smell test results within the population of Parkinsons patients admitted in Department of Neurology and Complementary medicine in Evangelical Hospital Hattingen from 2012 till 2017. Patients received the prescribed Allopathy and Ayurveda treatment for their ailments along with Ayurveda diet, Ayurveda massage and purification therapies. The primary and the only outcome measure was to assess the results of smelling sensation of the Parkinson’s patients already conducted by a Smell test with Sniffing Sticks supplied by Burghart Messtechnik. A paired t-test was conducted to compare scores obtained in smell test before and after treatment in each group separately. There was a significant difference in the scores of smell test in two groups. Results suggest that patients, treated first with Vasthi and then Ksheerabala oil Nasya showed significant improvement in the scores of smell test (t=-2.509, p= 0.017). The results of patients, treated with only Vasthi also showed significant improvement in the scores of smell test (t=-2.007, p= 0.053).

scholarly journals Alpha-Synuclein Disrupts Inter-Membrane Interactions

2019 ◽  
Vol 116 (3) ◽  
pp. 494a-495a
Author(s):  
Peter J. Chung ◽  
Qingteng Zhang ◽  
Hyeondo Luke Hwang ◽  
Alessandra Leong ◽  
Eric Dufresne ◽  
...  
Keyword(s):  
Alpha Synuclein ◽  
Membrane Interactions

scholarly journals Assessing the Structural Dynamics and Membrane Interactions of the Disordered Protein Alpha-Synuclein

2014 ◽  
Vol 106 (2) ◽  
pp. 267a-268a
Author(s):  
Michael M. Lacy ◽  
Vanessa C. Ducas ◽  
Anthony R. Braun ◽  
Jonathan N. Sachs ◽  
Elizabeth Rhoades
Keyword(s):  
Structural Dynamics ◽  
Alpha Synuclein ◽  
Membrane Interactions ◽  
Disordered Protein

scholarly journals Hsp70 chaperone blocks α-synuclein oligomer formation via a novel engagement mechanism

2020 ◽  
Author(s):  
Jiahui Tao ◽  
Amandine Berthet ◽  
Rose Citron ◽  
Robert Stanley ◽  
Jason Gestwicki ◽  
...  
Keyword(s):  
Substrate Binding ◽  
Alpha Synuclein ◽  
Early Event ◽  
Parkinsons Disease ◽  
Interaction Site ◽  
Over Expression ◽  
Oligomer Formation ◽  
Hsp70 Chaperone ◽  
Binding Cleft ◽  
Chaperone Hsp70

Over-expression and aggregation of alpha-synuclein (ASyn) are linked to the onset and pathology of Parkinsons disease and related synucleinopathies. Elevated levels of the stress induced chaperone, Hsp70, protects against ASyn misfolding and ASyn-driven neurodegeneration in cell and animal models, yet there is minimal mechanistic understanding of this important protective pathway. It is generally assumed that Hsp70 binds to ASyn using its canonical and promiscuous substrate-binding cleft to limit aggregation. Here we report that this activity is due to a novel and unexpected mode of Hsp70 action, involving neither ATP nor the typical substrate-binding cleft. We use novel ASyn oligomerization assays to show that Hsp70 directly blocks ASyn oligomerization, an early event in ASyn misfolding. Using truncations, mutations and inhibitors, we confirmed that Hsp70 interacts with ASyn via an as yet unidentified, non-canonical interaction site in the C-terminal domain. Finally, a biological role for a non-canonical interaction was observed in H4 neuroglioma cells. Together, these findings suggest that new chemical approaches will be required to target Hsp70-ASyn interaction in synucleinopathies. Such approaches are likely to be more specific than targeting Hsp70 canonical actions. Additionally, these results raise the question of whether other misfolded proteins might also engage via the same non-canonical mechanism.

scholarly journals Polarized α-synuclein trafficking and transcytosis across Brain Endothelial Cells via Rab7-decorated carriers

2021 ◽  
Author(s):  
Parvez Alam ◽  
Mikkel Roland Holst ◽  
Line Laursen ◽  
Janni Nielsen ◽  
Simone Nielsen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vesicular Transport ◽  
Alpha Synuclein ◽  
Brain Endothelial Cells ◽  
Direct Role ◽  
Peripheral Tissues ◽  
Parkinsons Disease ◽  
Therapeutic Implications ◽  
The Brain

Parkinsons disease is mainly caused by aggregation of alpha-synuclein (α-syn) in the brain. Exchange of α-syn between the brain and peripheral tissues could have important pathophysiological and therapeutic implications, but the trafficking mechanism of α-syn across the blood brain barrier (BBB) remains unclear. In this study, we therefore investigated uptake and transport mechanisms of α-syn monomers and oligomers across an in vitro BBB model system. Both α-syn monomers and oligomers were internalized by primary brain endothelial cells, with increased restriction of oligomeric over monomeric transport. To enlighten the trafficking route of monomeric α-syn in brain endothelial cells, we investigated co-localization of α-syn and intracellular markers of vesicular transport. Here, we observed the highest colocalization with clathrin, Rab7 and VPS35, suggesting a clathrin-dependent internalization, preferentially followed by a late endosome retromer-connected trafficking pathway. Furthermore, STED microscopy revealed monomeric α-syn trafficking via Rab7-decorated carriers. Knockdown of Caveolin1, VPS35, and Rab7 using siRNA did not affect monomeric α-syn uptake into endothelial cells. However, it significantly reduced transcytosis of monomeric α-syn in the luminal-abluminal direction, suggesting a polarized regulation of monomeric α-syn vesicular transport. Our findings suggest a direct role for Rab7 in polarized trafficking of monomeric α-syn across BBB endothelium, and the potential of Rab7 directed trafficking to constitute a target pathway for new therapeutic strategies against Parkinsons disease and related synucleinopathies.

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