Molecular Mechanism for the Suppression of Alpha Synuclein Membrane Toxicity by an Unconventional Extracellular Chaperone

2020 ◽  
Author(s):  
Rashik Ahmed ◽  
Jinfeng Huang ◽  
Daniel K. Weber ◽  
Tata Gopinath ◽  
Gianluigi Veglia ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Alpha Synuclein ◽  
Membrane Toxicity ◽  
Extracellular Chaperone

Aplp1 and the Aplp1-Lag3 Complex facilitates transmission of pathologic alpha-synuclein

2021 ◽  
Author(s):  
Xiaobo Mao ◽  
Hao Gu ◽  
Donghoon Kim ◽  
Yasuyoshi Kimura ◽  
Ning Wang ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Molecular Mechanism ◽  
Amyloid Beta ◽  
Dopaminergic Neurons ◽  
Lymphocyte Activation ◽  
Alpha Synuclein ◽  
Therapeutic Strategies ◽  
Behavioral Deficits ◽  
Lymphocyte Activation Gene

Pathologic alpha-synuclein (alpha-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid beta precursor-like protein 1 (Aplp1) forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic alpha-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by alpha-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of alpha-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by alpha-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for alpha-syn PFF induced pathology advances our understanding of the molecular mechanism of cell-to-cell transmission of pathologic alpha-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson disease and related alpha-synucleinopathies.

scholarly journals The Molecular Mechanism of Alpha-Synuclein Dependent Regulation of Protein Phosphatase 2A Activity

2018 ◽  
Vol 47 (6) ◽  
pp. 2613-2625 ◽  
Author(s):  
Jing Qu ◽  
Hongxia Yan ◽  
Yuan Zheng ◽  
Fenqin Xue ◽  
Yan Zheng ◽  
...  
Keyword(s):  
Affinity Chromatography ◽  
Molecular Mechanism ◽  
Protein Phosphatase ◽  
Colorimetric Assay ◽  
Protein Phosphatase 2A ◽  
Recombinant Baculovirus ◽  
Alpha Synuclein ◽  
Hydrophobic Domain ◽  
Pp2a Activity ◽  
Phosphatase 2A

Background/Aims: Alpha-synuclein (α-Syn) is a neuronal protein that is highly implicated in Parkinson’s disease (PD), and protein phosphatase 2A (PP2A) is an important serine/threonine phosphatase that is associated with neurodegenerative diseases, such as PD. α-Syn can directly upregulate PP2A activity, but the underling mechanism remains unclear. Therefore, we investigated the molecular mechanism of α-Syn regulating PP2A activity. Methods: α-Syn and its truncations were expressed in E.coli, and purified by affinity chromatography. PP2A Cα and its mutants were expressed in recombinant baculovirus, and purified by affinity chromatography combined with gel filtration chromatography. The interaction between α-Syn and PP2A Cα was detected by GST pull-down assay. PP2A activity was investigated by the colorimetric assay. Results: The hydrophobic non-amyloid component (NAC) domain of α-Syn interacted with PP2A Cα and upregulated its activity. α-Syn aggregates reduced its ability to upregulate PP2A activity, since the hydrophobic domain of α-Syn was blocked during aggregation. Furthermore, in the hydrophobic center of PP2A Cα, the residue of I123 was responsible for PP2A to interact with α-Syn, and its hydrophilic mutation blocked its interaction with α-Syn as well as its activity upregulation by α-Syn. Conclusions: α-Syn bound to PP2A Cα by the hydrophobic interaction and upregulated its activity. Blocking the hydrophobic domain of α-Syn or hydrophilic mutation on the residue I123 in PP2A Cα all reduced PP2A activity upregulation by α-Syn. Overall, we explored the mechanism of α-Syn regulating PP2A activity, which might offer much insight into the basis underlying PD pathogenesis.

Additional evidence for AQP1 vesicle trafficking as a molecular mechanism for ductal bile secretion

2001 ◽  
Vol 120 (5) ◽  
pp. A91-A91
Author(s):  
P TIETZ ◽  
P SPLINTER ◽  
M MCNIVEN ◽  
R HUEBERT ◽  
N LARUSSO
Keyword(s):  
Molecular Mechanism ◽  
Vesicle Trafficking ◽  
Bile Secretion

Hypoxia/Reoxygenation on human myometrial and decidual cells: A molecular mechanism involved in preterra labor

1998 ◽  
Vol 5 (1) ◽  
pp. 187A-187A
Author(s):  
J CARVAJAL ◽  
S KATO ◽  
J SAEZ ◽  
F LEIGHTON ◽  
G VALENZUELA ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Decidual Cells ◽  
Hypoxia Reoxygenation

Molecular Mechanism of Apoptosis Induction by Resveratrol, a Natural Cancer Chemopreventive Agent

2008 ◽  
Vol 78 (1) ◽  
pp. 3-8 ◽  
Author(s):  
Fan ◽  
Jiang ◽  
Zhang ◽  
Bai
Keyword(s):  
Cancer Treatment ◽  
Molecular Mechanism ◽  
Apoptosis Induction ◽  
Protective Agents ◽  
Chemopreventive Agent ◽  
Naturally Occurring ◽  
Apoptosis Pathways ◽  
Present Understanding

In efforts to identify naturally occurring compounds that act as protective agents, resveratrol, a phytoalexin existing in wine, has attracted much interest because of its diverse pharmacological characteristics. Considering that apoptosis induction is the most potent defense approach for cancer treatment, we have tried to summarize our present understanding of apoptosis induction by resveratrol based on the two major apoptosis pathways.

Chaperone mediated degradation of aggregated alpha synuclein

2004 ◽  
Vol 31 (S 1) ◽  
Author(s):  
J Klucken ◽  
Y Shin ◽  
PJ Mclean ◽  
BT Hyman
Keyword(s):  
Alpha Synuclein
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