scholarly journals α-Synuclein facilitates endocytosis by elevating the steady-state levels of phosphatidylinositol 4,5-bisphosphate

2020 ◽  
Author(s):  
Schechter Meir ◽  
Atias Merav ◽  
Abd Elhadi Suaad ◽  
Davidi Dana ◽  
Gitler Daniel ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Plasma Membrane ◽  
Membrane Trafficking ◽  
Synaptic Vesicles ◽  
Causative Role ◽  
Coated Pits ◽  
Exact Role ◽  
Intrinsically Disordered

Abstractα-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson’s disease (PD). It is an intrinsically disordered protein that binds acidic phospholipids. Growing evidence supports a role for α-Syn in membrane trafficking, including, mechanisms of endocytosis and exocytosis, although the exact role of α-Syn in these mechanisms is currently unclear. Here we have investigated the role of α-Syn in membrane trafficking through its association with acidic phosphoinositides (PIPs), such as phosphatidylinositol 4,5-bisphosphate (PI4,5P2) and phosphatidylinositol 3,4-bisphosphate (PI3,4P2). Our results show that α-Syn colocalizes with PIP2 and the phosphorylated active form of the clathrin adaptor AP2 at clathrin-coated pits. Using endocytosis of transferrin, an indicator of clathrin mediated endocytosis (CME), we find that α-Syn involvement in endocytosis is specifically mediated through PI4,5P2 levels. We further show that the rate of synaptic vesicle (SV) endocytosis is differentially affected by α-Syn mutations. In accord with their effects on PI4,5P2 levels at the plasma membrane, the PD associated E46K and A53T mutations further enhance SV endocytosis. However, neither A30P mutation, nor Lysine to Glutamic acid substitutions at the KTKEGV repeat domain of α-Syn, that interfere with phospholipid binding, affect SV endocytosis. This study provides evidence for a critical involvement of PIPs in α-Syn-mediated membrane trafficking.Significance Statementα-Synuclein (α-Syn) protein is known for its causative role in Parkinson’s disease. α-Syn is normally involved in mechanisms of membrane trafficking, including endocytosis, exocytosis and synaptic vesicles cycling. However, a certain degree of controversy regarding the exact role of α-Syn in these mechanisms persists. Here we show that α-Syn acts to increase plasma membrane levels PI4,5P2 and PI3,4P2 to facilitate clathrin mediated and synaptic vesicles endocytosis. Based on the results, we suggest that α-Syn interactions with the acidic phosphoinositides facilitate a shift in their homeostasis to support endocytosis.

Does human alpha synuclein behave like prions?

2021 ◽  
Vol 20 ◽  
Author(s):  
Yasir Hasan Siddique
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Synaptic Vesicles ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Present Review ◽  
Exact Role

: Alpha synuclein (α-synuclein) is a protein which is abundantly found in brain and in lesser amount in heart and muscles. The exact role of α-synuclein is not known but it is consider to control the movement of synaptic vesicles. Its overexpression in the neurons leads to the formation of Lewy bodies which specifically damage the dopaminergic neurons in the subtantianigra of the mid brain and leads to the progression of Parkinson’s disease (PD). There are evidences that aggregates of α-synuclein behaves like prions. The present review is an attempt to put forth the nature of α-synuclein as prions.

Structural Studies of Dynamin Tubular Crystals by Cryo-Electron Microscopy

1999 ◽  
Vol 5 (S2) ◽  
pp. 1024-1025
Author(s):  
Peijun Zhang ◽  
Jenny E. Hinshaw
Keyword(s):  
Plasma Membrane ◽  
Membrane Trafficking ◽  
Lipid Vesicles ◽  
Coated Vesicle ◽  
Permissive Temperature ◽  
Coated Pits ◽  
Unique Role ◽  
Cryo Electron Microscopy ◽  
Tubular Crystals

Dynamin is a 100 kD GTPase that plays an essential role in clathrin-coated vesicle formation during receptor mediated endocytosis, and in caveolae internalization and may play a role in intracellular membrane trafficking (1). It shares an extensive sequence homology (70% identity) to shibiregene product in Drosophila(2,3). The shibiretsmutants exhibit a rapid and reversible paralysis at non-permissive temperature due to a depletion of synaptic vesicles in their nerve termini which is believed to be caused by a block in endocytosis since there is an accumulation of “collared” clathrin-coated pits at the plasma membrane (4). Synaptosomes treated with GTPγs produces elongated necks surrounded by dynamin (6). Purified recombinant dynamin itself can assemble to form spirals and bind to lipid vesicles to form tubes, which resemble the “collar” at the necks of coated pits (5). These dynamin tubes vesiculate upon GTP treatment (7), suggesting a unique role of dynamin acting as a mechanoenzyme which causes clathrin-coated vesicles to be pinched off plasma membrane.

scholarly journals Structural basis of synaptic vesicle assembly promoted by α-synuclein

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Giuliana Fusco ◽  
Tillmann Pape ◽  
Amberley D. Stephens ◽  
Pierre Mahou ◽  
Ana Rita Costa ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Synaptic Vesicle ◽  
Synaptic Vesicles ◽  
Lewy Bodies ◽  
Intrinsically Disordered Protein ◽  
Structural Basis ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Familial Parkinson’S Disease

Abstractα-synuclein (αS) is an intrinsically disordered protein whose fibrillar aggregates are the major constituents of Lewy bodies in Parkinson’s disease. Although the specific function of αS is still unclear, a general consensus is forming that it has a key role in regulating the process of neurotransmitter release, which is associated with the mediation of synaptic vesicle interactions and assembly. Here we report the analysis of wild-type αS and two mutational variants linked to familial Parkinson’s disease to describe the structural basis of a molecular mechanism enabling αS to induce the clustering of synaptic vesicles. We provide support for this ‘double-anchor’ mechanism by rationally designing and experimentally testing a further mutational variant of αS engineered to promote stronger interactions between synaptic vesicles. Our results characterize the nature of the active conformations of αS that mediate the clustering of synaptic vesicles, and indicate their relevance in both functional and pathological contexts.

scholarly journals ADORA2A rs5760423 and CYP1A2 rs762551 Polymorphisms as Risk Factors for Parkinson’s Disease

2021 ◽  
Vol 10 (3) ◽  
pp. 381 ◽  
Author(s):  
Vasileios Siokas ◽  
Athina-Maria Aloizou ◽  
Zisis Tsouris ◽  
Ioannis Liampas ◽  
Panagiotis Liakos ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Basis ◽  
Genetic Model ◽  
Healthy Controls ◽  
Exact Role ◽  
Negative Results ◽  
Meta Analyses

Background: Parkinson’s disease (PD) is the second commonest neurodegenerative disease. The genetic basis of PD is indisputable. Both ADORA2A rs5760423 and CYP1A2 rs762551 have been linked to PD, to some extent, but the exact role of those polymorphisms in PD remains controversial. Objective: We assessed the role of ADORA2A rs5760423 and CYP1A2 rs762551 on PD risk. Methods: We genotyped 358 patients with PD and 358 healthy controls for ADORA2A rs5760423 and CYP1A2 rs762551. We also merged and meta-analyzed our data with data from previous studies, regarding these two polymorphisms and PD. Results: No significant association with PD was revealed (p > 0.05), for either ADORA2A rs5760423 or CYP1A2 rs762551, in any of the examined genetic model of inheritance. In addition, results from meta-analyses yield negative results. Conclusions: Based on our analyses, it appears rather unlikely that ADORA2A rs5760423 or CYP1A2 rs762551 is among the major risk factors for PD, at least in Greek patients with PD.

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