Special Issue "Key Signalling Molecules in Aging and Neurodegeneration"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling and Regulated Cell Death".

Deadline for manuscript submissions: 31 December 2019.

Special Issue Editors

Guest Editor
Prof. Paola Pizzo Website E-Mail
Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
Interests: Ca2+ homeostasis; mitochondria; endoplasmic reticulum; oraganelle contact sites; MAM; bioenergetics; Alzheimer's disease; presenilin; neurodegeneration
Assistant Guest Editor
Dr. Riccardo Filadi Website E-Mail
Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy
Interests: Ca2+ homeostasis; Alzheimer's disease; presenilin; neurodegeneration; mitochondria; endoplasmic reticulum; oraganelle contact sites; MAM; bioenergetics

Special Issue Information

Dear Colleagues,

The human lifespan has drastically increased in the past decades and the percentage of the aged population is constantly rising, posing major health and economic challenges. Aging invariably increases the risk of several diseases, such as those linked to neurodegeneration, cancer, stroke and diabetes. In this Special Issue, the focus will be on neurodegenerative disorders of the elderly, particularly Parkinson and Alzheimer diseases. Both conditions are characterized by the progressive degeneration of specific neuronal circuits, through largely unknown pathogenic mechanisms, and are devoid of valid therapeutic approaches. Therefore, the need to find novel targets and early biomarkers to develop appropriate pharmacological strategies appears urgent. In this scenario, precise knowledge of the specific cellular and molecular processes behind aging and neurodegeneration is a priority for the scientific community.
The aim of this Special Issue is to provide an overview of the main signalling pathways and molecules involved in the process of aging, highlighting their intimate connection with the onset of neurodegenerative disorders.

Prof. Paola Pizzo
Dr. Riccardo Filadi
Guest Editors

Manuscript Submission Information

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Keywords

  • aging
  • neurodegeneration
  • calcium
  • oxidative stress
  • cAMP
  • mitochondria
  • proteostasis
  • autophagy
  • immunity
  • inflammation
  • senescence
  • ER stress
  • UPR
  • Alzheimer
  • metabolism

Published Papers (6 papers)

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Research

Open AccessArticle
Deregulated miR-29b-3p Correlates with Tissue-Specific Activation of Intrinsic Apoptosis in An Animal Model of Amyotrophic Lateral Sclerosis
Cells 2019, 8(9), 1077; https://doi.org/10.3390/cells8091077 - 12 Sep 2019
Abstract
Amyotrophic lateral sclerosis (ALS) is one of the most common incurable motor neuron disorders in adults. The majority of all ALS cases occur sporadically (sALS). Symptoms of ALS are caused by a progressive degeneration of motor neurons located in the motor cortex and [...] Read more.
Amyotrophic lateral sclerosis (ALS) is one of the most common incurable motor neuron disorders in adults. The majority of all ALS cases occur sporadically (sALS). Symptoms of ALS are caused by a progressive degeneration of motor neurons located in the motor cortex and spinal cord. The question arises why motor neurons selectively degenerate in ALS, while other cells and systems appear to be spared the disease. Members of the intrinsic apoptotic pathway are frequent targets of altered microRNA expression. Therefore, microRNAs and their effects on cell survival are subject of controversial debates. In this study, we investigated the expression of numerous members of the intrinsic apoptotic cascade by qPCR, western blot, and immunostaining in two different regions of the CNS of wobbler mice. Further we addressed the expression of miR-29b-3p targeting BMF, Bax, and, Bak, members of the apoptotic pathway. We show a tissue-specific differential expression of BMF, Bax, and cleaved-Caspase 3 in wobbler mice. An opposing regulation of miR-29b-3p expression in the cerebellum and cervical spinal cord of wobbler mice suggests different mechanisms regulating the intrinsic apoptotic pathway. Based on our findings, it could be speculated that miR-29b-3p might regulate antiapoptotic survival mechanisms in CNS areas that are not affected by neurodegeneration in the wobbler mouse ALS model. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
Free-Water Imaging in White and Gray Matter in Parkinson’s Disease
Cells 2019, 8(8), 839; https://doi.org/10.3390/cells8080839 - 05 Aug 2019
Abstract
This study aimed to discriminate between neuroinflammation and neuronal degeneration in the white matter (WM) and gray matter (GM) of patients with Parkinson’s disease (PD) using free-water (FW) imaging. Analysis using tract-based spatial statistics (TBSS) of 20 patients with PD and 20 healthy [...] Read more.
This study aimed to discriminate between neuroinflammation and neuronal degeneration in the white matter (WM) and gray matter (GM) of patients with Parkinson’s disease (PD) using free-water (FW) imaging. Analysis using tract-based spatial statistics (TBSS) of 20 patients with PD and 20 healthy individuals revealed changes in FW imaging indices (i.e., reduced FW-corrected fractional anisotropy (FAT), increased FW-corrected mean, axial, and radial diffusivities (MDT, ADT, and RDT, respectively) and fractional volume of FW (FW) in somewhat more specific WM areas compared with the changes of DTI indices. The region-of-interest (ROI) analysis further supported these findings, whereby those with PD showed significantly lower FAT and higher MDT, ADT, and RDT (indices of neuronal degeneration) in anterior WM areas as well as higher FW (index of neuroinflammation) in posterior WM areas compared with the controls. Results of GM-based spatial statistics (GBSS) analysis revealed that patients with PD had significantly higher MDT, ADT, and FW than the controls, whereas ROI analysis showed significantly increased MDT and FW and a trend toward increased ADT in GM areas, corresponding to Braak stage IV. These findings support the hypothesis that neuroinflammation precedes neuronal degeneration in PD, whereas WM microstructural alterations precede changes in GM. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
Isomerization of Asp7 in Beta-Amyloid Enhances Inhibition of the α7 Nicotinic Receptor and Promotes Neurotoxicity
Cells 2019, 8(8), 771; https://doi.org/10.3390/cells8080771 - 25 Jul 2019
Abstract
Cholinergic dysfunction in Alzheimer’s disease (AD) can be mediated by the neuronal α7 nicotinic acetylcholine receptor (α7nAChR). Beta-amyloid peptide (Aβ) binds to the α7nAChR, disrupting the receptor’s function and causing neurotoxicity. In vivo not only Aβ but also its modified forms can drive [...] Read more.
Cholinergic dysfunction in Alzheimer’s disease (AD) can be mediated by the neuronal α7 nicotinic acetylcholine receptor (α7nAChR). Beta-amyloid peptide (Aβ) binds to the α7nAChR, disrupting the receptor’s function and causing neurotoxicity. In vivo not only Aβ but also its modified forms can drive AD pathogenesis. One of these forms, iso-Aβ (containing an isomerized Asp7 residue), shows an increased neurotoxicity in vitro and stimulates amyloidogenesis in vivo. We suggested that such effects of iso-Aβ are α7nAChR-dependent. Here, using calcium imaging and electrophysiology, we found that iso-Aβ is a more potent inhibitor of the α7nAChR-mediated calcium current than unmodified Aβ. However, Asp7 isomerization eliminated the ability of Aβ to decrease the α7nAChR levels. These data indicate differences in the interaction of the peptides with the α7nAChR, which we demonstrated using computer modeling. Neither Aβ nor iso-Aβ competed with 125I-α-bungarotoxin for binding to the orthosteric site of the receptor, suggesting the allosteric binging mode of the peptides. Further we found that increased neurotoxicity of iso-Aβ was mediated by the α7nAChR. Thus, the isomerization of Asp7 enhances the inhibitory effect of Aβ on the functional activity of the α7nAChR, which may be an important factor in the disruption of the cholinergic system in AD. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles
Cells 2019, 8(6), 597; https://doi.org/10.3390/cells8060597 - 15 Jun 2019
Cited by 2
Abstract
The maintenance of muscle mass and its ability to function relies on a bioenergetic efficient mitochondrial network. This network is highly impacted by fusion and fission events. We have recently shown that the acute deletion of the fusion protein Opa1 induces muscle atrophy, [...] Read more.
The maintenance of muscle mass and its ability to function relies on a bioenergetic efficient mitochondrial network. This network is highly impacted by fusion and fission events. We have recently shown that the acute deletion of the fusion protein Opa1 induces muscle atrophy, systemic inflammatory response, precocious epithelial senescence, and premature death that are caused by muscle-dependent secretion of FGF21. However, both fusion and fission machinery are suppressed in aging sarcopenia, cancer cachexia, and chemotherapy-induced muscle wasting. We generated inducible muscle-specific Opa1 and Drp1 double-knockout mice to address the physiological relevance of the concomitant impairment of fusion and fission machinery in skeletal muscle. Here we show that acute ablation of Opa1 and Drp1 in adult muscle causes the accumulation of abnormal and dysfunctional mitochondria, as well as the inhibition of autophagy and mitophagy pathways. This ultimately results in ER stress, muscle loss, and the reduction of force generation. However, the simultaneous inhibition of the fission protein Drp1 when Opa1 is absent alleviates FGF21 induction, oxidative stress, denervation, and inflammation rescuing the lethal phenotype of Opa1 knockout mice, despite the presence of any muscle weakness. Thus, the simultaneous inhibition of fusion and fission processes mitigates the detrimental effects of unbalanced mitochondrial fusion and prevents the secretion of pro-senescence factors. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
pHluorin-BACE1-mCherry Acts as a Reporter for the Intracellular Distribution of Active BACE1 In Vitro and In Vivo
Cells 2019, 8(5), 474; https://doi.org/10.3390/cells8050474 - 17 May 2019
Cited by 2
Abstract
β-site APP-cleaving enzyme 1 (BACE1) initiates amyloid precursor protein (APP) cleavage and β-amyloid (Aβ) production, a critical step in the pathogenesis of Alzheimer’s disease (AD). It is thus of considerable interest to investigate how BACE1 activity is regulated. BACE1 has its maximal activity [...] Read more.
β-site APP-cleaving enzyme 1 (BACE1) initiates amyloid precursor protein (APP) cleavage and β-amyloid (Aβ) production, a critical step in the pathogenesis of Alzheimer’s disease (AD). It is thus of considerable interest to investigate how BACE1 activity is regulated. BACE1 has its maximal activity at acidic pH and GFP variant—pHluorin—displays pH dependence. In light of these observations, we generated three tandem fluorescence-tagged BACE1 fusion proteins, named pHluorin-BACE1-mCherry, BACE1-mCherry-pHluorin and BACE1-mCherry-EGFP. Comparing the fluorescence characteristics of these proteins in response to intracellular pH changes induced by chloroquine or bafilomycin A1, we found that pHluorin-BACE1-mCherry is a better pH sensor for BACE1 because its fluorescence intensity responds to pH changes more dramatically and more quickly. Additionally, we found that (pro)renin receptor (PRR), a subunit of the v-ATPase complex, which is critical for maintaining vesicular pH, regulates pHluorin’s fluorescence and BACE1 activity in pHluorin-BACE1-mCherry expressing cells. Finally, we found that the expression of Swedish mutant APP (APPswe) suppresses pHluorin fluorescence in pHluorin-BACE1-mCherry expressing cells in culture and in vivo, implicating APPswe not only as a substrate but also as an activator of BACE1. Taken together, these results suggest that the pHluorin-BACE1-mCherry fusion protein may serve as a useful tool for visualizing active/inactive BACE1 in culture and in vivo. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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Open AccessArticle
Genetic and Real-World Clinical Data, Combined with Empirical Validation, Nominate Jak-Stat Signaling as a Target for Alzheimer’s Disease Therapeutic Development
Cells 2019, 8(5), 425; https://doi.org/10.3390/cells8050425 - 08 May 2019
Abstract
As genome-wide association studies (GWAS) have grown in size, the number of genetic variants that have been associated per disease has correspondingly increased. Despite this increase in the number of single-nucleotide polymorphisms (SNPs) identified per disease, their biological interpretation has in many cases [...] Read more.
As genome-wide association studies (GWAS) have grown in size, the number of genetic variants that have been associated per disease has correspondingly increased. Despite this increase in the number of single-nucleotide polymorphisms (SNPs) identified per disease, their biological interpretation has in many cases remained elusive. To address this, we have combined GWAS results with orthogonal sources of evidence, namely the current knowledge of molecular pathways; real-world clinical data from six million patients; RNA expression across tissues from Alzheimer’s disease (AD) patients, and purpose-built rodent models for experimental validation. In more detail, first we show that when examined at a pathway level, analysis of all GWAS studies groups AD in a cluster with disorders of immunity and inflammation. Using clinical data, we show that the degree of comorbidity of these diseases with AD correlates with the strength of their genetic association with molecular participants in the Janus kinases/signal transducer and activator of transcription (JAK-STAT) pathway. Using four independent RNA expression datasets we then find evidence for the altered regulation of JAK-STAT pathway genes in AD. Finally, we use both in vitro and in vivo rodent models to demonstrate that Aβ induces gene expression of the key drivers of this pathway, providing experimental evidence to validate these data-driven observations. These results therefore nominate JAK-STAT anomalies as a prominent aetiopathological event in AD and hence a potential target for therapeutic development, and moreover demonstrate a de novo multi-modal approach to derive information from rapidly increasing genomic datasets. Full article
(This article belongs to the Special Issue Key Signalling Molecules in Aging and Neurodegeneration)
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