Regulation of Exocytosis and Mitochondrial Relocalization by Alpha-Synuclein in a Mammalian Cell Model

Ramezani, Meraj; Wilkes, Marcus; Das, Tapojyoti; Holowka, David; Eliezer, David; Baird, Barbara

doi:10.1101/492066

Cited by 2 publications

(2 citation statements)

References 102 publications

(126 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alpha-synuclein aggregation is a pathological hallmark of PD. Emerging evidence has shown that alphasynuclein has profound functions at the mitochondria or to impact mitochondria, including mitochondrial oxidative phosphorylation, dynamics, mitophagy, Ca 2+ , and iron homeostasis 8,34,[59][60][61][62][63][64] .…”

Section: Discussionmentioning

confidence: 99%

A Mitochondrial Inside-Out Iron-Calcium Signal Reveals Drug Targets for Parkinson’s Disease

Bharat

Vanhauwaert

et al. 2022

Preprint

View full text Add to dashboard Cite

Genetic backgrounds and risk factors among individuals with Parkinson disease (PD) are highly heterogenous, limiting our ability to effectively detect and treat PD. Here we connect several potential PD risk genes and elements to one biological pathway. Elevation of Fe2+-levels causes Ca2+-overflow into the mitochondria, through an interaction of Fe2+ with mitochondrial calcium uniporter (MCU), the Ca2+-import channel in the inner mitochondrial membrane, and resultant MCU oligomerization. This mechanism acts in PD neuron models and postmortem brains. Miro, a Ca2+-binding protein, functions downstream of Ca2+-dysregulation, and holds promise to classify PD status and monitor drug efficacy in human blood cells. Polygenetic enrichment of rare, non-synonymous variants in this iron-calcium-Miro axis influences PD risk. This axis can be targeted by multiple ways to prevent neurodegeneration in PD models. Our results show a linear pathway linking several PD risk factors, which can be leveraged for genetic counseling, risk evaluation, and therapeutic strategies.

show abstract

Section: Discussionmentioning

confidence: 99%

A Mitochondrial Inside-Out Iron-Calcium Signal Reveals Drug Targets for Parkinson’s Disease

Bharat

Vanhauwaert

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Especially interesting are studies about the role of endocytosis in the electroporation-induced transport of genetic material to the cells [80][81][82] . The only studies concerning the electroporation-induced release of vesicles concern the joining of the cells with the intracellular vesicles and thus the release of chromogranin A and other excretory proteins 82,83 . To further investigate the MAGE antigens localization in the tumor-like environment, we applied confocal microscopy of 3D melanoma cell culture models.…”

Section: Discussionmentioning

confidence: 99%

Pulsed electric field induces exocytosis and overexpression of MAGE antigens in melanoma

Szlasa,

Sauer,

Baczyńska

et al. 2024

Sci Rep

View full text Add to dashboard Cite

Nanosecond pulsed electric field (nsPEF) has emerged as a promising approach for inducing cell death in melanoma, either as a standalone treatment or in combination with chemotherapeutics. However, to date, there has been a shortage of studies exploring the impact of nsPEF on the expression of cancer-specific molecules. In this investigation, we sought to assess the effects of nsPEF on melanoma-specific MAGE (Melanoma Antigen Gene Protein Family) expression. To achieve this, melanoma cells were exposed to nsPEF with parameters set at 8 kV/cm, 200 ns duration, 100 pulses, and a frequency of 10 kHz. We also aimed to comprehensively describe the consequences of this electric field on melanoma cells' invasion and proliferation potential. Our findings reveal that following exposure to nsPEF, melanoma cells release microvesicles containing MAGE antigens, leading to a simultaneous increase in the expression and mRNA content of membrane-associated antigens such as MAGE-A1. Notably, we observed an unexpected increase in the expression of PD-1 as well. While we did not observe significant differences in the cells' proliferation or invasion potential, a remarkable alteration in the cells' metabolomic and lipidomic profiles towards a less aggressive phenotype was evident. Furthermore, we validated these results using ex vivo tissue cultures and 3D melanoma culture models. Our study demonstrates that nsPEF can elevate the expression of membrane-associated proteins, including melanoma-specific antigens. The mechanism underlying the overexpression of MAGE antigens involves the initial release of microvesicles containing MAGE antigens, followed by a gradual increase in mRNA levels, ultimately resulting in elevated expression of MAGE antigens post-experiment. These findings shed light on a novel method for modulating cancer cells to overexpress cancer-specific molecules, thereby potentially enhancing their sensitivity to targeted anticancer therapy.

show abstract

Regulation of Exocytosis and Mitochondrial Relocalization by Alpha-Synuclein in a Mammalian Cell Model

Cited by 2 publications

References 102 publications

A Mitochondrial Inside-Out Iron-Calcium Signal Reveals Drug Targets for Parkinson’s Disease

A Mitochondrial Inside-Out Iron-Calcium Signal Reveals Drug Targets for Parkinson’s Disease

Pulsed electric field induces exocytosis and overexpression of MAGE antigens in melanoma

Contact Info

Product

Resources

About