Plasmalemmal VDAC-1 corroborated as amyloid Aß-receptor

Thinnes, Friedrich P.

doi:10.3389/fnagi.2015.00188

Cited by 6 publications

(5 citation statements)

References 40 publications

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“…VDACs are a family of proteins present on the mitochondrial outer membrane, on which they supply diffusion pores for small hydrophilic molecules and are involved in the release of cytochrome c at the onset of apoptotic cell death. Interestingly, recent evidence suggests that VDAC could be involved in the pathogenesis of several syndromes, including autism [44,45,46]. In particular, Gonzalez-Gronow and colleagues identified the presence of autoantibodies against VDAC proteins in autistic individuals, suggesting their possible causal role in the neurologic pathogenesis of autism [44].…”

Section: Discussionmentioning

confidence: 99%

Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene

Bacchelli

Loi

Cameli

et al. 2019

JCM

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Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with high heritability, although their underlying genetic factors are still largely unknown. Here we present a comprehensive genetic characterization of two ASD siblings from Sardinia by genome-wide copy number variation analysis and whole exome sequencing (WES), to identify novel genetic alterations associated with this disorder. Single nucleotide polymorphism (SNP) array data revealed a rare microdeletion involving CAPG, ELMOD3, and SH2D6 genes, in both siblings. CAPG encodes for a postsynaptic density (PSD) protein known to regulate spine morphogenesis and synaptic formation. The reduced CAPG mRNA and protein expression levels in ASD patients, in the presence of hemizygosity or a particular genetic and/or epigenetic background, highlighted the functional relevance of CAPG as a candidate gene for ASD. WES analysis led to the identification in both affected siblings of a rare frameshift mutation in VDAC3, a gene intolerant to loss of function mutation, encoding for a voltage-dependent anion channel localized on PSD. Moreover, four missense damaging variants were identified in genes intolerant to loss of function variation encoding for PSD proteins: PLXNA2, KCTD16, ARHGAP21, and SLC4A1. This study identifies CAPG and VDAC3 as candidate genes and provides additional support for genes encoding PSD proteins in ASD susceptibility.

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Section: Discussionmentioning

confidence: 99%

Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene

Bacchelli

Loi

Cameli

et al. 2019

JCM

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“…This interaction occurs for both the putative plasma membrane (discussed below) VDAC1 and mitochondrial VDAC1. It is worth noting that Aβ interaction with plasma membrane VDAC facilitates penetration of Aβ into the cell (Thinnes, 2015a , b ). At the mitochondrial level, Aβ interaction with VDAC1 results in the detachment of the anti-apoptotic protein, HK, an increase in channel conductance likely by inducing VDAC1 oligomerization, and cytochrome c release (Reddy, 2013a , b ).…”

Section: Role Of Vdac In Neurodegenerative Diseasesmentioning

confidence: 99%

“…Nonetheless, in those cells where the channel has been identified in the plasma membrane, some functional roles have been suggested (De Pinto et al, 2010b ). As alluded above (Role of VDAC in Neurodegenerative Disease), plasma membrane VDAC has also been implicated in the transport of Aβ into the cell (Thinnes, 2015b ). The study showed that silencing VDAC1 expression by siRNA prevented Aβ entry into the cytosol and prevented cytotoxicity.…”

Section: Does Vdac Exist In the Plasma Membrane?mentioning

confidence: 99%

Mitochondrial VDAC1: A Key Gatekeeper as Potential Therapeutic Target

et al. 2017

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Mitochondria are the key source of ATP that fuels cellular functions, and they are also central in cellular signaling, cell division and apoptosis. Dysfunction of mitochondria has been implicated in a wide range of diseases, including neurodegenerative and cardiac diseases, and various types of cancer. One of the key proteins that regulate mitochondrial function is the voltage-dependent anion channel 1 (VDAC1), the most abundant protein on the outer membrane of mitochondria. VDAC1 is the gatekeeper for the passages of metabolites, nucleotides, and ions; it plays a crucial role in regulating apoptosis due to its interaction with apoptotic and anti-apoptotic proteins, namely members of the Bcl-2 family of proteins and hexokinase. Therefore, regulation of VDAC1 is crucial not only for metabolic functions of mitochondria, but also for cell survival. In fact, multiple lines of evidence have confirmed the involvement of VDAC1 in several diseases. Consequently, modulation or dysregulation of VDAC1 function can potentially attenuate or exacerbate pathophysiological conditions. Understanding the role of VDAC1 in health and disease could lead to selective protection of cells in different tissues and diverse diseases. The purpose of this review is to discuss the role of VDAC1 in the pathogenesis of diseases and as a potentially effective target for therapeutic management of various pathologies.

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“…Indeed, it has been suggested that dissociation from ERα favors the progressive dephosphorylation of pl-VDAC and its proapoptotic activation. This promotes its physical association with βA, which results in increased neuronal vulnerability (Herrera et al, 2011a ; Fernandez-Echevarria et al, 2014 ; Smilansky et al, 2015 ; Thinnes, 2015a , b ; Canerina-Amaro et al, 2017 ). This suggests that estrogen binding to ERα signalosome may be part of the mechanisms of neuroprotection against Aβ production, and that progressive VDAC dephosphorylation and trafficking out of raft microdomains may be part of the neurotoxic mechanism that exacerbates AD progression.…”

Section: Discussionmentioning

confidence: 99%

Neuronal ER-Signalosome Proteins as Early Biomarkers in Prodromal Alzheimer's Disease Independent of Amyloid-β Production and Tau Phosphorylation

Mesa-Herrera

Marín

Torrealba

et al. 2022

Front. Mol. Neurosci.

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There exists considerable interest to unveil preclinical period and prodromal stages of Alzheimer's disease (AD). The mild cognitive impairment (MCI) is characterized by significant memory and/or other cognitive domains impairments, and is often considered the prodromal phase of AD. The cerebrospinal fluid (CSF) levels of β-amyloid (βA), total tau (t-tau), and phosphorylated tau (p-tau) have been used as biomarkers of AD albeit their significance as indicators during early stages of AD remains far from accurate. The new biomarkers are being intensively sought as to allow identification of pathological processes underlying early stages of AD. Fifty-three participants (75.4 ± 8.3 years) were classified in three groups as cognitively normal healthy controls (HC), MCI, and subjective memory complaints (SMC). The subjects were subjected to a battery of neurocognitive tests and underwent lumbar puncture for CSF extraction. The CSF levels of estrogen-receptor (ER)-signalosome proteins, βA, t-tau and p-tau, were submitted to univariate, bivariate, and multivariate statistical analyses. We have found that the components of the ER-signalosome, namely, caveolin-1, flotilin-1, and estrogen receptor alpha (ERα), insulin growth factor-1 receptor β (IGF1Rβ), prion protein (PrP), and plasmalemmal voltage dependent anion channel 1 (VDAC) could be detected in the CSF from all subjects of the HC, MCI, and SMC groups. The six proteins appeared elevated in MCI and slightly increased in SMC subjects compared to HC, suggesting that signalosome proteins undergo very early modifications in nerve cells. Using a multivariate approach, we have found that the combination of ERα, IGF-1Rβ, and VDAC are the main determinants of group segregation with resolution enough to predict the MCI stage. The analyses of bivariate relationships indicated that collinearity of ER-signalosome proteins vary depending on the stage, with some pairs displaying opposed relationships between HC and MCI groups, and the SMC stage showing either no relationships or behaviors similar to either HC or MCI stages. The multinomial logistic regression models of changes in ER-signalosome proteins provide reliable predictive criteria, particularly for the MCI. Notably, most of the statistical analyses revealed no significant relationships or interactions with classical AD biomarkers at either disease stage. Finally, the multivariate functions were highly correlated with outcomes from neurocognitive tests for episodic memory. These results demonstrate that alterations in ER-signalosome might provide useful diagnostic information on preclinical stages of AD, independently from classical biomarkers.

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Plasmalemmal VDAC-1 corroborated as amyloid Aß-receptor

Cited by 6 publications

References 40 publications

Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene

Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene

Mitochondrial VDAC1: A Key Gatekeeper as Potential Therapeutic Target

Neuronal ER-Signalosome Proteins as Early Biomarkers in Prodromal Alzheimer's Disease Independent of Amyloid-β Production and Tau Phosphorylation

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