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30 pages, 9150 KiB

Open AccessArticle

Antioxidants Prevent Iron Accumulation and Lipid Peroxidation, but Do Not Correct Autophagy Dysfunction or Mitochondrial Bioenergetics in Cellular Models of BPAN

by Alejandra Suárez-Carrillo, Mónica Álvarez-Córdoba, Ana Romero-González, Marta Talaverón-Rey, Suleva Povea-Cabello, Paula Cilleros-Holgado, Rocío Piñero-Pérez, Diana Reche-López, David Gómez-Fernández, José Manuel Romero-Domínguez, Manuel Munuera-Cabeza, Antonio Díaz, Susana González-Granero, José Manuel García-Verdugo and José A. Sánchez-Alcázar

Int. J. Mol. Sci. 2023, 24(19), 14576; https://doi.org/10.3390/ijms241914576 - 26 Sep 2023

Cited by 2 | Viewed by 1931

Abstract

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic disorders frequently associated with iron accumulation in the basal nuclei of the brain. Among NBIA subtypes, β-propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The [...] Read more.

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic disorders frequently associated with iron accumulation in the basal nuclei of the brain. Among NBIA subtypes, β-propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate the autophagic defects and secondary pathological consequences in cellular models derived from two patients harboring WDR45 mutations. Both protein and mRNA expression levels of WDR45 were decreased in patient-derived fibroblasts. In addition, the increase of LC3B upon treatments with autophagy inducers or inhibitors was lower in mutant cells compared to control cells, suggesting decreased autophagosome formation and impaired autophagic flux. A transmission electron microscopy (TEM) analysis showed mitochondrial vacuolization associated with the accumulation of lipofuscin-like aggregates containing undegraded material. Autophagy dysregulation was also associated with iron accumulation and lipid peroxidation. In addition, mutant fibroblasts showed altered mitochondrial bioenergetics. Antioxidants such as pantothenate, vitamin E and α-lipoic prevented lipid peroxidation and iron accumulation. However, antioxidants were not able to correct the expression levels of WDR45, neither the autophagy defect nor cell bioenergetics. Our study demonstrated that WDR45 mutations in BPAN cellular models impaired autophagy, iron metabolism and cell bioenergetics. Antioxidants partially improved cell physiopathology; however, autophagy and cell bioenergetics remained affected. Full article

(This article belongs to the Special Issue Neurodegeneration 2022: From Genetics to Molecules)

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18 pages, 3185 KiB

Open AccessArticle

Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration

by Yu-Hao Lin, Yao-Hsiang Shih, Ye Vone Yap, Yen-Wei Chen, Hsiang-Lin Kuo, Tsung-Yun Liu, Li-Jin Hsu, Yu-Min Kuo and Nan-Shan Chang

Int. J. Mol. Sci. 2022, 23(23), 14510; https://doi.org/10.3390/ijms232314510 - 22 Nov 2022

Cited by 3 | Viewed by 2072

Abstract

When WWOX is downregulated in middle age, aggregation of a protein cascade, including TRAPPC6AΔ (TPC6AΔ), TIAF1, and SH3GLB2, may start to occur, and the event lasts more than 30 years, which results in amyloid precursor protein (APP) degradation, amyloid beta (Aβ) generation, and [...] Read more.

When WWOX is downregulated in middle age, aggregation of a protein cascade, including TRAPPC6AΔ (TPC6AΔ), TIAF1, and SH3GLB2, may start to occur, and the event lasts more than 30 years, which results in amyloid precursor protein (APP) degradation, amyloid beta (Aβ) generation, and neurodegeneration, as shown in Alzheimer’s disease (AD). Here, by treating neuroblastoma SK-N-SH cells with neurotoxin MPP+, upregulation and aggregation of TPC6AΔ, along with aggregation of TIAF1, SH3GLB2, Aβ, and tau, occurred. MPP+ is an inducer of Parkinson’s disease (PD), suggesting that TPC6AΔ is a common initiator for AD and PD pathogenesis. Zfra, a 31-amino-acid zinc finger-like WWOX-binding protein, is known to restore memory deficits in 9-month-old triple-transgenic (3xTg) mice by blocking the aggregation of TPC6AΔ, SH3GLB2, tau, and amyloid β, as well as inflammatory NF-κB activation. The Zfra4-10 peptide exerted a strong potency in preventing memory loss during the aging of 3-month-old 3xTg mice up to 9 months, as determined by a novel object recognition task (ORT) and Morris water maize analysis. Compared to age-matched wild type mice, 11-month-old Wwox heterozygous mice exhibited memory loss, and this correlates with pT12-WWOX aggregation in the cortex. Together, aggregation of pT12-WWOX may link to TPC6AΔ aggregation for AD progression, with TPC6AΔ aggregation being a common initiator for AD and PD progression. Full article

(This article belongs to the Special Issue Neurodegeneration 2022: From Genetics to Molecules)

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17 pages, 15684 KiB

Open AccessArticle

Interactions between C8orf37 and FAM161A, Two Ciliary Proteins Essential for Photoreceptor Survival

by Yu Liu, Jinjun Chen, Rachel Sager, Erika Sasaki and Huaiyu Hu

Int. J. Mol. Sci. 2022, 23(19), 12033; https://doi.org/10.3390/ijms231912033 - 10 Oct 2022

Cited by 1 | Viewed by 1831

Abstract

Mutations in C8orf37 cause Bardet-Biedl syndrome (BBS), retinitis pigmentosa (RP), and cone–rod dystrophy (CRD), all manifest in photoreceptor degeneration. Little is known about which proteins C8orf37 interacts with to contribute to photoreceptor survival. To determine the proteins that potentially interact with C8orf37, we [...] Read more.

Mutations in C8orf37 cause Bardet-Biedl syndrome (BBS), retinitis pigmentosa (RP), and cone–rod dystrophy (CRD), all manifest in photoreceptor degeneration. Little is known about which proteins C8orf37 interacts with to contribute to photoreceptor survival. To determine the proteins that potentially interact with C8orf37, we carried out a yeast two-hybrid (Y2H) screen using C8orf37 as a bait. FAM161A, a microtubule-binding protein localized at the photoreceptor cilium required for photoreceptor survival, was identified as one of the preys. Double immunofluorescence staining and proximity ligation assay (PLA) of marmoset retinal sections showed that C8orf37 was enriched and was co-localized with FAM161A at the ciliary base of photoreceptors. Epitope-tagged C8orf37 and FAM161A, expressed in HEK293 cells, were also found to be co-localized by double immunofluorescence staining and PLA. Furthermore, interaction domain mapping assays identified that the N-terminal region of C8orf37 and amino acid residues 341-517 within the PFAM UPF0564 domain of FAM161A were critical for C8orf37–FAM161A interaction. These data suggest that the two photoreceptor survival proteins, C8orf37 and FAM161A, interact with each other which may contribute to photoreceptor health. Full article

(This article belongs to the Special Issue Neurodegeneration 2022: From Genetics to Molecules)

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22 pages, 7479 KiB

Open AccessArticle

Selective Calpain Inhibition Improves Functional and Histopathological Outcomes in a Canine Spinal Cord Injury Model

by Elsayed Metwally, Hatim A. Al-Abbadi, Mohamed A. Hashem, Yasmina K. Mahmoud, Eman A. Ahmed, Ahmed I. Maaty, Ibrahim E. Helal and Mahmoud F. Ahmed

Int. J. Mol. Sci. 2022, 23(19), 11772; https://doi.org/10.3390/ijms231911772 - 4 Oct 2022

Cited by 5 | Viewed by 2307

Abstract

Calpain activation has been implicated in various pathologies, including neurodegeneration. Thus, calpain inhibition could effectively prevent spinal cord injury (SCI) associated with neurodegeneration. In the current study, a dog SCI model was used to evaluate the therapeutic potential of a selective calpain inhibitor [...] Read more.

Calpain activation has been implicated in various pathologies, including neurodegeneration. Thus, calpain inhibition could effectively prevent spinal cord injury (SCI) associated with neurodegeneration. In the current study, a dog SCI model was used to evaluate the therapeutic potential of a selective calpain inhibitor (PD150606) in combination with methylprednisolone sodium succinate (MPSS) as an anti-inflammatory drug. SCI was experimentally induced in sixteen mongrel dogs through an epidural balloon compression technique. The dogs were allocated randomly into four groups: control, MPSS, PD150606, and MPSS+PD150606. Clinical evaluation, serum biochemical, somatosensory evoked potentials, histopathological, and immunoblotting analyses were performed to assess treated dogs during the study. The current findings revealed that the combined administration of MPSS+PD150606 demonstrated considerably lower neuronal loss and microglial cell infiltration than the other groups, with a significant improvement in the locomotor score. The increased levels of inflammatory markers (GFAP and CD11) and calcium-binding proteins (Iba1 and S100) were significantly reduced in the combination group and to a lesser extent in MPSS or PD150606 treatment alone. Interestingly, the combined treatment effectively inhibited the calpain-induced cleavage of p35, limited cdk5 activation, and inhibited tau phosphorylation. These results suggest that early MPSS+PD150606 therapy after acute SCI may prevent subsequent neurodegeneration via calpain inhibition. Full article

(This article belongs to the Special Issue Neurodegeneration 2022: From Genetics to Molecules)

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16 pages, 4949 KiB

Open AccessArticle

Exercise Normalized the Hippocampal Renin-Angiotensin System and Restored Spatial Memory Function, Neurogenesis, and Blood-Brain Barrier Permeability in the 2K1C-Hypertensive Mouse

by Ying-Shuang Chang, Chih-Lung Lin, Chu-Wan Lee, Han-Chen Lin, Yi-Ting Wu and Yao-Hsiang Shih

Int. J. Mol. Sci. 2022, 23(10), 5531; https://doi.org/10.3390/ijms23105531 - 16 May 2022

Cited by 2 | Viewed by 2187

Abstract

Hypertension is associated with blood-brain barrier alteration and brain function decline. Previously, we established the 2-kidney,1-clip (2K1C) hypertensive mice model by renin-angiotensin system (RAS) stimulating. We found that 2K1C-induced hypertension would impair hippocampus-related memory function and decrease adult hippocampal neurogenesis. Even though large [...] Read more.

Hypertension is associated with blood-brain barrier alteration and brain function decline. Previously, we established the 2-kidney,1-clip (2K1C) hypertensive mice model by renin-angiotensin system (RAS) stimulating. We found that 2K1C-induced hypertension would impair hippocampus-related memory function and decrease adult hippocampal neurogenesis. Even though large studies have investigated the mechanism of hypertension affecting brain function, there remains a lack of efficient ways to halt this vicious effect. The previous study indicated that running exercise ameliorates neurogenesis and spatial memory function in aging mice. Moreover, studies showed that exercise could normalize RAS activity, which might be associated with neurogenesis impairment. Thus, we hypothesize that running exercise could ameliorate neurogenesis and spatial memory function impairment in the 2K1C-hypertension mice. In this study, we performed 2K1C surgery on eight-weeks-old C57BL/6 mice and put them on treadmill exercise one month after the surgery. The results indicate that running exercise improves the spatial memory and neurogenesis impairment of the 2K1C-mice. Moreover, running exercise normalized the activated RAS and blood-brain barrier leakage of the hippocampus, although the blood pressure was not decreased. In conclusion, running exercise could halt hypertension-induced brain impairment through RAS normalization. Full article

(This article belongs to the Special Issue Neurodegeneration 2022: From Genetics to Molecules)

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25 pages, 1666 KiB

Open AccessReview

A Promising Strategy to Treat Neurodegenerative Diseases by SIRT3 Activation

by Alpna Tyagi and Subbiah Pugazhenthi

Int. J. Mol. Sci. 2023, 24(2), 1615; https://doi.org/10.3390/ijms24021615 - 13 Jan 2023

Cited by 8 | Viewed by 4717

Abstract

SIRT3, the primary mitochondrial deacetylase, regulates the functions of mitochondrial proteins including metabolic enzymes and respiratory chain components. Although SIRT3’s functions in peripheral tissues are well established, the significance of its downregulation in neurodegenerative diseases is beginning to emerge. SIRT3 plays a key [...] Read more.

SIRT3, the primary mitochondrial deacetylase, regulates the functions of mitochondrial proteins including metabolic enzymes and respiratory chain components. Although SIRT3’s functions in peripheral tissues are well established, the significance of its downregulation in neurodegenerative diseases is beginning to emerge. SIRT3 plays a key role in brain energy metabolism and provides substrate flexibility to neurons. It also facilitates metabolic coupling between fuel substrate-producing tissues and fuel-consuming tissues. SIRT3 mediates the health benefits of lifestyle-based modifications such as calorie restriction and exercise. SIRT3 deficiency is associated with metabolic syndrome (MetS), a precondition for diseases including obesity, diabetes, and cardiovascular disease. The pure form of Alzheimer’s disease (AD) is rare, and it has been reported to coexist with these diseases in aging populations. SIRT3 downregulation leads to mitochondrial dysfunction, neuroinflammation, and inflammation, potentially triggering factors of AD pathogenesis. Recent studies have also suggested that SIRT3 may act through multiple pathways to reduce plaque formation in the AD brain. In this review, we give an overview of SIRT3’s roles in brain physiology and pathology and discuss several activators of SIRT3 that can be considered potential therapeutic agents for the treatment of dementia. Full article

(This article belongs to the Special Issue Neurodegeneration 2022: From Genetics to Molecules)

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21 pages, 1999 KiB

Open AccessReview

Modeling of Neurodegenerative Diseases: ‘Step by Step’ and ‘Network’ Organization of the Complexes of Model Systems

by Viacheslav Igorevich Pasko, Aleksandra Sergeevna Churkina, Anton Sergeevich Shakhov, Anatoly Alexeevich Kotlobay and Irina Borisovna Alieva

Int. J. Mol. Sci. 2023, 24(1), 604; https://doi.org/10.3390/ijms24010604 - 29 Dec 2022

Cited by 4 | Viewed by 1847

Abstract

Neurodegenerative diseases have acquired the status of one of the leading causes of death in developed countries, which requires creating new model systems capable of accurately reproducing the mechanisms underlying these pathologies. Here we analyzed modern model systems and their contribution to the [...] Read more.

Neurodegenerative diseases have acquired the status of one of the leading causes of death in developed countries, which requires creating new model systems capable of accurately reproducing the mechanisms underlying these pathologies. Here we analyzed modern model systems and their contribution to the solution of unexplored manifestations of neuropathological processes. Each model has unique properties that make it the optimal tool for modeling certain aspects of neurodegenerative disorders. We concluded that to optimize research, it is necessary to combine models into complexes that include organisms and artificial systems of different organizational levels. Such complexes can be organized in two ways. The first method can be described as “step by step”, where each model for studying a certain characteristic is a separate step that allows using the information obtained in the modeling process for the gradual study of increasingly complex processes in subsequent models. The second way is a ‘network’ approach. Studies are carried out with several types of models simultaneously, and experiments with each specific type are adjusted in conformity with the data obtained from other models. In our opinion, the ‘network‘ approach to combining individual model systems seems more promising for fundamental biology as well as diagnostics and therapy. Full article

(This article belongs to the Special Issue Neurodegeneration 2022: From Genetics to Molecules)

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17 pages, 380 KiB

Open AccessReview

Gut Microbiota and Immunotherapy for Alzheimer’s Disease

by Chun-Ling Dai, Fei Liu, Khalid Iqbal and Cheng-Xin Gong

Int. J. Mol. Sci. 2022, 23(23), 15230; https://doi.org/10.3390/ijms232315230 - 3 Dec 2022

Cited by 7 | Viewed by 2658

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that eventually leads to dementia and death of the patient. Currently, no effective treatment is available that can slow or halt the progression of the disease. The gut microbiota can modulate the host immune system [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that eventually leads to dementia and death of the patient. Currently, no effective treatment is available that can slow or halt the progression of the disease. The gut microbiota can modulate the host immune system in the peripheral and central nervous system through the microbiota–gut–brain axis. Growing evidence indicates that gut microbiota dysbiosis plays an important role in the pathogenesis of AD, and modulation of the gut microbiota may represent a new avenue for treating AD. Immunotherapy targeting Aβ and tau has emerged as the most promising disease-modifying therapy for the treatment of AD. However, the underlying mechanism of AD immunotherapy is not known. Importantly, preclinical and clinical studies have highlighted that the gut microbiota exerts a major influence on the efficacy of cancer immunotherapy. However, the role of the gut microbiota in AD immunotherapy has not been explored. We found that immunotherapy targeting tau can modulate the gut microbiota in an AD mouse model. In this article, we focused on the crosstalk between the gut microbiota, immunity, and AD immunotherapy. We speculate that modulation of the gut microbiota induced by AD immunotherapy may partially underlie the efficacy of the treatment. Full article

(This article belongs to the Special Issue Neurodegeneration 2022: From Genetics to Molecules)

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