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21 pages, 2536 KiB

Open AccessArticle

Vitronectin and Its Interaction with PAI-1 Suggests a Functional Link to Vascular Changes in AMD Pathobiology

by Fabiola Biasella, Tobias Strunz, Christina Kiel, on behalf of the International AMD Genomics Consortium (IAMDGC), Bernhard H. F. Weber and Ulrike Friedrich

Cells 2022, 11(11), 1766; https://doi.org/10.3390/cells11111766 - 27 May 2022

Cited by 4 | Viewed by 2784

Abstract

The pathogenesis of age-related macular degeneration (AMD), a frequent disorder of the central retina, is incompletely understood. Genome-wide association studies (GWAS) suggest a strong contribution of genomic variation in AMD susceptibility. Nevertheless, little is known about biological mechanisms of the disease. We reported [...] Read more.

The pathogenesis of age-related macular degeneration (AMD), a frequent disorder of the central retina, is incompletely understood. Genome-wide association studies (GWAS) suggest a strong contribution of genomic variation in AMD susceptibility. Nevertheless, little is known about biological mechanisms of the disease. We reported previously that the AMD-associated polymorphism rs704C > T in the vitronectin (VTN) gene influences protein expression and functional aspects of encoded vitronectin, a human blood and extracellular matrix (ECM) protein. Here, we refined the association of rs704 with AMD in 16,144 cases and 17,832 controls and noted that rs704 is carried exclusively by the neovascular AMD subtype. Interaction studies demonstrate that rs704 affects the ability of vitronectin to bind the angiogenic regulator plasminogen activator inhibitor 1 (PAI-1) but has no influence on stabilizing its active state. Western blot analysis and confocal imaging reveal a strong enrichment of PAI-1 in the ECM of cultured endothelial cells and RPE cell line ARPE-19 exposed to vitronectin. Large-scale gene expression of VTN and PAI-1 showed positive correlations and a statistically significant increase in human retinal and blood tissues aged 60 years and older. Our results suggest a mechanism by which the AMD-associated rs704 variant in combination with ageing may contribute to the vascular complications in AMD. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Updates and Challenges)

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16 pages, 4020 KiB

Open AccessArticle

Effects of Epigenetic Modification of PGC-1α by a Chemical Chaperon on Mitochondria Biogenesis and Visual Function in Retinitis Pigmentosa

by Yoko Ozawa, Eriko Toda, Kohei Homma, Hideto Osada, Norihiro Nagai, Kazuo Tsubota and Hideyuki Okano

Cells 2022, 11(9), 1497; https://doi.org/10.3390/cells11091497 - 29 Apr 2022

Cited by 7 | Viewed by 2561

Abstract

Retinitis pigmentosa (RP) is a hereditary blinding disease characterized by gradual photoreceptor death, which lacks a definitive treatment. Here, we demonstrated the effect of 4-phenylbutyric acid (PBA), a chemical chaperon that can suppress endoplasmic reticulum (ER) stress, in P23H mutant rhodopsin knock-in RP [...] Read more.

Retinitis pigmentosa (RP) is a hereditary blinding disease characterized by gradual photoreceptor death, which lacks a definitive treatment. Here, we demonstrated the effect of 4-phenylbutyric acid (PBA), a chemical chaperon that can suppress endoplasmic reticulum (ER) stress, in P23H mutant rhodopsin knock-in RP models. In the RP models, constant PBA treatment led to the retention of a greater number of photoreceptors, preserving the inner segment (IS), a mitochondrial- and ER-rich part of the photoreceptors. Electroretinography showed that PBA treatment preserved photoreceptor function. At the early point, ER-associated degradation markers, xbp1s, vcp, and derl1, mitochondrial kinetic-related markers, fis1, lc3, and mfn1 and mfn2, as well as key mitochondrial regulators, pgc-1α and tfam, were upregulated in the retina of the models treated with PBA. In vitro analyses showed that PBA upregulated pgc-1α and tfam transcription, leading to an increase in the mitochondrial membrane potential, cytochrome c oxidase activity, and ATP levels. Histone acetylation of the PGC-1α promoter was increased by PBA, indicating that PBA affected the mitochondrial condition through epigenetic changes. Our findings constituted proof of concept for the treatment of ER stress-related RP using PBA and revealed PBA’s neuroprotective effects, paving the way for its future clinical application. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Updates and Challenges)

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29 pages, 3056 KiB

Open AccessArticle

Neurotoxic Astrocytes Directly Converted from Sporadic and Familial ALS Patient Fibroblasts Reveal Signature Diversities and miR-146a Theragnostic Potential in Specific Subtypes

by Cátia Gomes, Catarina Sequeira, Shibi Likhite, Cassandra N. Dennys, Stephen J. Kolb, Pamela J. Shaw, Ana R. Vaz, Brian K. Kaspar, Kathrin Meyer and Dora Brites

Cells 2022, 11(7), 1186; https://doi.org/10.3390/cells11071186 - 1 Apr 2022

Cited by 13 | Viewed by 3984

Abstract

A lack of stratification methods in patients with amyotrophic lateral sclerosis (ALS) is likely implicated in therapeutic failures. Regional diversities and pathophysiological abnormalities in astrocytes from mice with SOD1 mutations (mSOD1-ALS) can now be explored in human patients using somatic cell reprogramming. Here, [...] Read more.

A lack of stratification methods in patients with amyotrophic lateral sclerosis (ALS) is likely implicated in therapeutic failures. Regional diversities and pathophysiological abnormalities in astrocytes from mice with SOD1 mutations (mSOD1-ALS) can now be explored in human patients using somatic cell reprogramming. Here, fibroblasts from four sporadic (sALS) and three mSOD1-ALS patients were transdifferentiated into induced astrocytes (iAstrocytes). ALS iAstrocytes were neurotoxic toward HB9-GFP mouse motor neurons (MNs) and exhibited subtype stratification through GFAP, CX43, Ki-67, miR-155 and miR-146a expression levels. Up- (two cases) and down-regulated (three cases) miR-146a values in iAstrocytes were recapitulated in their secretome, either free or as cargo in small extracellular vesicles (sEVs). We previously showed that the neuroprotective phenotype of depleted miR-146 mSOD1 cortical astrocytes was reverted by its mimic. Thus, we tested such modulation in the most miR-146a-depleted patient-iAstrocytes (one sALS and one mSOD1-ALS). The miR-146a mimic in ALS iAstrocytes counteracted their reactive/inflammatory profile and restored miR-146a levels in sEVs. A reduction in lysosomal activity and enhanced synaptic/axonal transport-related genes in NSC-34 MNs occurred after co-culture with miR-146a-modulated iAstrocytes. In summary, the regulation of miR-146a in depleted ALS astrocytes may be key in reestablishing their normal function and in restoring MN lysosomal/synaptic dynamic plasticity in disease sub-groups. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Updates and Challenges)

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Review

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26 pages, 3176 KiB

Open AccessReview

PICALM and Alzheimer’s Disease: An Update and Perspectives

by Kunie Ando, Siranjeevi Nagaraj, Fahri Küçükali, Marie-Ange de Fisenne, Andreea-Claudia Kosa, Emilie Doeraene, Lidia Lopez Gutierrez, Jean-Pierre Brion and Karelle Leroy

Cells 2022, 11(24), 3994; https://doi.org/10.3390/cells11243994 - 10 Dec 2022

Cited by 23 | Viewed by 4219

Abstract

Genome-wide association studies (GWAS) have identified the PICALM (Phosphatidylinositol binding clathrin-assembly protein) gene as the most significant genetic susceptibility locus after APOE and BIN1. PICALM is a clathrin-adaptor protein that plays a critical role in clathrin-mediated endocytosis and autophagy. Since the effects [...] Read more.

Genome-wide association studies (GWAS) have identified the PICALM (Phosphatidylinositol binding clathrin-assembly protein) gene as the most significant genetic susceptibility locus after APOE and BIN1. PICALM is a clathrin-adaptor protein that plays a critical role in clathrin-mediated endocytosis and autophagy. Since the effects of genetic variants of PICALM as AD-susceptibility loci have been confirmed by independent genetic studies in several distinct cohorts, there has been a number of in vitro and in vivo studies attempting to elucidate the underlying mechanism by which PICALM modulates AD risk. While differential modulation of APP processing and Aβ transcytosis by PICALM has been reported, significant effects of PICALM modulation of tau pathology progression have also been evidenced in Alzheimer’s disease models. In this review, we summarize the current knowledge about PICALM, its physiological functions, genetic variants, post-translational modifications and relevance to AD pathogenesis. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Updates and Challenges)

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21 pages, 1916 KiB

Open AccessReview

Crosstalk between the Hippo Pathway and the Wnt Pathway in Huntington’s Disease and Other Neurodegenerative Disorders

by Pasquale Sileo, Clémence Simonin, Patricia Melnyk, Marie-Christine Chartier-Harlin and Philippe Cotelle

Cells 2022, 11(22), 3631; https://doi.org/10.3390/cells11223631 - 16 Nov 2022

Cited by 8 | Viewed by 3537

Abstract

The Hippo pathway consists of a cascade of kinases that controls the phosphorylation of the co-activators YAP/TAZ. When unphosphorylated, YAP and TAZ translocate into the nucleus, where they mainly bind to the TEAD transcription factor family and activate genes related to cell proliferation [...] Read more.

The Hippo pathway consists of a cascade of kinases that controls the phosphorylation of the co-activators YAP/TAZ. When unphosphorylated, YAP and TAZ translocate into the nucleus, where they mainly bind to the TEAD transcription factor family and activate genes related to cell proliferation and survival. In this way, the inhibition of the Hippo pathway promotes cell survival, proliferation, and stemness fate. Another pathway can modulate these processes, namely the Wnt/β-catenin pathway that is indeed involved in cellular functions such as proliferation and cell survival, as well as apoptosis, growth, and cell renewal. Wnt signaling can act in a canonical or noncanonical way, depending on whether β-catenin is involved in the process. In this review, we will focus only on the canonical Wnt pathway. It has emerged that YAP/TAZ are components of the β-catenin destruction complex and that there is a close relationship between the Hippo pathway and the canonical Wnt pathway. Furthermore, recent data have shown that both of these pathways may play a role in neurodegenerative diseases, such as Huntington’s disease, Alzheimer’s disease, or Amyotrophic Lateral Sclerosis. Thus, this review analyzes the Hippo pathway and the Wnt pathway, their crosstalk, and their involvement in Huntington’s disease, as well as in other neurodegenerative disorders. Altogether, these data suggest possible therapeutic approaches targeting key players of these pathways. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Updates and Challenges)

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21 pages, 921 KiB

Open AccessReview

GSK3 Is a Central Player in Retinal Degenerative Diseases but a Challenging Therapeutic Target

by Catherine Hottin, Muriel Perron and Jérôme E. Roger

Cells 2022, 11(18), 2898; https://doi.org/10.3390/cells11182898 - 16 Sep 2022

Cited by 4 | Viewed by 2817

Abstract

Glycogen synthase kinase 3 (GSK3) is a key regulator of many cellular signaling processes and performs a wide range of biological functions in the nervous system. Due to its central role in numerous cellular processes involved in cell degeneration, a rising number of [...] Read more.

Glycogen synthase kinase 3 (GSK3) is a key regulator of many cellular signaling processes and performs a wide range of biological functions in the nervous system. Due to its central role in numerous cellular processes involved in cell degeneration, a rising number of studies have highlighted the interest in developing therapeutics targeting GSK3 to treat neurodegenerative diseases. Although recent works strongly suggest that inhibiting GSK3 might also be a promising therapeutic approach for retinal degenerative diseases, its full potential is still under-evaluated. In this review, we summarize the literature on the role of GSK3 on the main cellular functions reported as deregulated during retinal degeneration, such as glucose homeostasis which is critical for photoreceptor survival, or oxidative stress, a major component of retinal degeneration. We also discuss the interest in targeting GSK3 for its beneficial effects on inflammation, for reducing neovascularization that occurs in some retinal dystrophies, or for cell-based therapy by enhancing Müller glia cell proliferation in diseased retina. Together, although GSK3 inhibitors hold promise as therapeutic agents, we highlight the complexity of targeting such a multitasked kinase and the need to increase our knowledge of the impact of reducing GSK3 activity on these multiple cellular pathways and biological processes. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Updates and Challenges)

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21 pages, 1717 KiB

Open AccessReview

The Impact of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis

by Jiantao Zhao, Xuemei Wang, Zijun Huo, Yanchun Chen, Jinmeng Liu, Zhenhan Zhao, Fandi Meng, Qi Su, Weiwei Bao, Lingyun Zhang, Shuang Wen, Xin Wang, Huancai Liu and Shuanhu Zhou

Cells 2022, 11(13), 2049; https://doi.org/10.3390/cells11132049 - 28 Jun 2022

Cited by 33 | Viewed by 4147

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and highly fatal neurodegenerative disease. Although the pathogenesis of ALS remains unclear, increasing evidence suggests that a key contributing factor is mitochondrial dysfunction. Mitochondria are organelles in eukaryotic cells responsible for bioenergy production, cellular metabolism, [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and highly fatal neurodegenerative disease. Although the pathogenesis of ALS remains unclear, increasing evidence suggests that a key contributing factor is mitochondrial dysfunction. Mitochondria are organelles in eukaryotic cells responsible for bioenergy production, cellular metabolism, signal transduction, calcium homeostasis, and immune responses and the stability of their function plays a crucial role in neurons. A single disorder or defect in mitochondrial function can lead to pathological changes in cells, such as an impaired calcium buffer period, excessive generation of free radicals, increased mitochondrial membrane permeability, and oxidative stress (OS). Recent research has also shown that these mitochondrial dysfunctions are also associated with pathological changes in ALS and are believed to be commonly involved in the pathogenesis of the disease. This article reviews the latest research on mitochondrial dysfunction and its impact on the progression of ALS, with specific attention to the potential of novel therapeutic strategies targeting mitochondrial dysfunction. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Updates and Challenges)

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24 pages, 946 KiB

Open AccessReview

Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia

by Liriopé Toupenet Marchesi, Marion Leblanc and Giovanni Stevanin

Cells 2021, 10(7), 1678; https://doi.org/10.3390/cells10071678 - 2 Jul 2021

Cited by 18 | Viewed by 5063

Abstract

Hereditary spastic paraplegia (HSP) refers to a group of neurological disorders involving the degeneration of motor neurons. Due to their clinical and genetic heterogeneity, finding common effective therapeutics is difficult. Therefore, a better understanding of the common pathological mechanisms is necessary. The role [...] Read more.

Hereditary spastic paraplegia (HSP) refers to a group of neurological disorders involving the degeneration of motor neurons. Due to their clinical and genetic heterogeneity, finding common effective therapeutics is difficult. Therefore, a better understanding of the common pathological mechanisms is necessary. The role of several HSP genes/proteins is linked to the endolysosomal and autophagic pathways, suggesting a functional convergence. Furthermore, impairment of these pathways is particularly interesting since it has been linked to other neurodegenerative diseases, which would suggest that the nervous system is particularly sensitive to the disruption of the endolysosomal and autophagic systems. In this review, we will summarize the involvement of HSP proteins in the endolysosomal and autophagic pathways in order to clarify their functioning and decipher some of the pathological mechanisms leading to HSP. Full article

(This article belongs to the Special Issue Neurodegenerative Diseases: Updates and Challenges)

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