Hsp90 and its co-chaperone Sti1 control TDP-43 misfolding and toxicity

AbstractProtein misfolding is a central feature of most neurodegenerative diseases. Molecular chaperones can modulate the toxicity associated with protein misfolding, but it remains elusive which molecular chaperones and co-chaperones interact with specific misfolded proteins. TDP-43 misfolding and inclusion formation is a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Using yeast and mammalian neuronal cells we find that Hsp90 and its co-chaperones have a strong capacity to alter TDP-43 misfolding, inclusion formation, aggregation, and cellular toxicity. Our data also demonstrate that impaired Hsp90 function sensitizes cells to TDP-43 toxicity. We further show that the co-chaperone Sti1 specifically interacts with and modulates TDP-43 toxicity in a dose-dependent manner. Our study thus uncovers a previously unrecognized tie between Hsp90, Sti1, TDP-43 misfolding, and its cellular toxicity.

Download Full-text

UBQLN2 Promotes the Production of Type I Interferon via the TBK1-IRF3 Pathway

Cells ◽

10.3390/cells9051205 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1205

Author(s):

Tianhong Chen ◽

Wenjuan Zhang ◽

Bo Huang ◽

Xuan Chen ◽

Cao Huang

Keyword(s):

Inflammatory Cytokines ◽

Type I Interferon ◽

Complete Loss ◽

Functional Assay ◽

Type I ◽

Dependent Manner ◽

Frontotemporal Degeneration ◽

Dose Dependent ◽

Lateral Sclerosis ◽

Pro Inflammatory Cytokines

Mutations of Ubiquilin 2 (UBQLN2) or TANK-binding kinase 1 (TBK1) are associated with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD). However, the mechanisms whereby UBQLN2 or TBK1 mutations lead to ALS and FTD remain unclear. Here, we explored the effect of UBQLN2 on TBK1 in HEK-293T cells or in CRISPR–Cas9-mediated IRF3 and IRF7 knockout (KO) cells. We found an interaction between TBK1 and UBQLN2, which was affected by ALS/FTD-linked mutations in TBK1 or UBQLN2. Co-expression of UBQLN2 with TBK1 elevated the protein level of TBK1 as well as the phosphorylation of TBK1 and IRF3 in a UBQLN2 dose-dependent manner, and this phosphorylation was reduced by mutant UBQLN2. In addition, the cellular production of IFN1 and related pro-inflammatory cytokines was substantially elevated when UBQLN2 and TBK1 were co-expressed, which was also decreased by mutant UBQLN2. Functional assay revealed that mutant UBQLN2 significantly reduced the binding affinity of TBK1 for its partners, including IRF3, (SQSTM1)/p62 and optineurin (OPTN). Moreover, complete loss of IRF3 abolished the induction of IFN1 and related pro-inflammatory cytokines enhanced by UBQLN2 in HEK-293T cells, whereas no significant change in IRF7 knockout cells was observed. Thus, our findings suggest that UBQLN2 promotes IRF3 phosphorylation via TBK1, leading to enhanced IFN1 induction, and also imply that the dysregulated TBK1-IRF3 pathway may play a role in UBQLN2-related neurodegeneration.

Download Full-text

Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper

Antioxidants ◽

10.3390/antiox9111113 ◽

2020 ◽

Vol 9 (11) ◽

pp. 1113

Author(s):

Pamela Maher

Keyword(s):

Transition Metals ◽

Neurodegenerative Diseases ◽

Dependent Manner ◽

Copper Binding ◽

Drug Candidates ◽

Beneficial Effects ◽

Anti Inflammatory ◽

Dose Dependent

Alterations occur in the homeostasis of the transition metals iron (Fe2+) and copper (Cu2+) during aging and these are further amplified in neurodegenerative diseases, including Alzheimer’s disease (AD). These observations suggest that the most effective drug candidates for AD might be those that can reduce these alterations. The flavonoid fisetin has both neuroprotective and anti-inflammatory activity both in vitro and in vivo and can bind both iron and copper suggesting that its chelating activity might play a role in its beneficial effects. To test this idea, the effects of iron and copper on both the neuroprotective and anti-inflammatory activities of fisetin were examined. It is shown that while fisetin can reduce the potentiation of cell death by iron and copper in response to treatments that lower glutathione levels, it is much less effective when the metals are combined with other inducers of oxidative stress. In addition, iron but not copper reduces the anti-inflammatory effects of fisetin in a dose-dependent manner. These effects correlate with the ability of iron but not copper to block the induction of the antioxidant transcription factor, Nrf2, by fisetin. In contrast, although the flavanone sterubin also binds iron, the metal has no effect on sterubin’s ability to induce Nrf2 or protect cells from toxic or pro-inflammatory insults. Together, these results suggest that while iron and copper binding could contribute to the beneficial effects of neuroprotective compounds in the context of neurodegenerative diseases, the consequences of this binding need to be fully examined for each compound.

Download Full-text

The Functional Roles of Curcumin on Astrocytes in Neurodegenerative Diseases

NeuroImmunoModulation ◽

10.1159/000517901 ◽

2021 ◽

pp. 1-11

Author(s):

Amir Mohammadi ◽

Abasalt Hosseinzadeh Colagar ◽

Ayeh Khorshidian ◽

Seyed Mohammad Amini

Keyword(s):

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Essential Role ◽

Neurological Dysfunction ◽

Therapeutic Effects ◽

Functional Roles ◽

Correct Function ◽

The Central Nervous System ◽

Lateral Sclerosis ◽

Brain Homeostasis

Progressive abnormality and loss of axons and neurons in the central nervous system (CNS) cause neurodegenerative diseases (NDs). Protein misfolding and its collection are the most important pathological features of NDs. Astrocytes are the most plentiful cells in the mammalian CNS (about 20–40% of the human brain) and have several central functions in the maintenance of the health and correct function of the CNS. Astrocytes have an essential role in the preservation of brain homeostasis, and it is not surprising that these multifunctional cells have been implicated in the onset and progression of several NDs. Thus, they become an exciting target for the study of NDs. Over almost 15 years, it was revealed that curcumin has several therapeutic effects in a wide variety of diseases’ treatment. Curcumin is a valuable ingredient present in turmeric spice and has several essential roles, including those which are anticarcinogenic, hepatoprotective, thrombosuppressive, cardioprotective, anti-arthritic, anti-inflammatory, antioxidant, chemopreventive, chemotherapeutic, and anti-infectious. Furthermore, curcumin can suppress inflammation; promote angiogenesis; and treat diabetes, pulmonary problems, and neurological dysfunction. Here, we review the effects of curcumin on astrocytes in NDs, with a focus on Alzheimer’s disease, Parkinson’s disease, multiple scleroses, Huntington’s disease, and amyotrophic lateral sclerosis.

Download Full-text

Bentonite Exposure in Western Pacific Amyotrophic Lateral Sclerosis/ Parkinsonism Dementia Complex and Neurodegenerative Diseases

10.20944/preprints202005.0507.v1 ◽

2020 ◽

Author(s):

Kavitha Reddy

Keyword(s):

Risk Factors ◽

Amyotrophic Lateral Sclerosis ◽

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Western Pacific ◽

Lateral Sclerosis

Neurodegenerative diseases of protein misfolding affect humans and animals. In humans, these diseases include Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Western Pacific amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC). Mineral exposure may be important in the pathogenesis of protein misfolding cascades. The possible association of bentonite, montmorillonite, and mineral risk factors with Alzheimer’s disease, Parkinson’s disease, ALS, and Western Pacific ALS/PDC is analyzed and discussed.

Download Full-text

Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases

Cells ◽

10.3390/cells9102183 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2183

Author(s):

Tuuli-Maria Sonninen ◽

Gundars Goldsteins ◽

Nihay Laham-Karam ◽

Jari Koistinaho ◽

Šárka Lehtonen

Keyword(s):

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Inflammatory Responses ◽

Biological Response ◽

Protein Damage ◽

Protein Homeostasis ◽

Cellular Functions ◽

Regenerative Capacity ◽

Age Related ◽

Lateral Sclerosis

Protein homeostasis (proteostasis) disturbances and inflammation are evident in normal aging and some age-related neurodegenerative diseases. While the proteostasis network maintains the integrity of intracellular and extracellular functional proteins, inflammation is a biological response to harmful stimuli. Cellular stress conditions can cause protein damage, thus exacerbating protein misfolding and leading to an eventual overload of the degradation system. The regulation of proteostasis network is particularly important in postmitotic neurons due to their limited regenerative capacity. Therefore, maintaining balanced protein synthesis, handling unfolding, refolding, and degrading misfolded proteins are essential to preserve all cellular functions in the central nervous sysytem. Failing proteostasis may trigger inflammatory responses in glial cells, and the consequent release of inflammatory mediators may lead to disturbances in proteostasis. Here, we review the mechanisms of proteostasis and inflammatory response, emphasizing their role in the pathological hallmarks of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Furthermore, we discuss the interplay between proteostatic stress and excessive immune response that activates inflammation and leads to dysfunctional proteostasis.

Download Full-text

Protein misfolding in the late-onset neurodegenerative diseases: Common themes and the unique case of amyotrophic lateral sclerosis

Proteins Structure Function and Bioinformatics ◽

10.1002/prot.24285 ◽

2013 ◽

Vol 81 (8) ◽

pp. 1285-1303 ◽

Cited By ~ 56

Author(s):

Vikram Khipple Mulligan ◽

Avijit Chakrabartty

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Late Onset ◽

Unique Case ◽

Lateral Sclerosis

Download Full-text

Chikusetsu saponin V attenuates H2O2-induced oxidative stress in human neuroblastoma SH-SY5Y cells through Sirt1/PGC-1α/Mn-SOD signaling pathways

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2015-0262 ◽

2016 ◽

Vol 94 (9) ◽

pp. 919-928 ◽

Cited By ~ 20

Author(s):

Jingzhi Wan ◽

Lili Deng ◽

Changcheng Zhang ◽

Qin Yuan ◽

Jing Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Neurodegenerative Diseases ◽

Signaling Pathways ◽

Vital Role ◽

Dependent Manner ◽

Neuroprotective Effects ◽

Human Neuroblastoma ◽

Ros Accumulation ◽

Antioxidative Effects ◽

Dose Dependent

Oxidative stress plays a vital role in the pathogenesis of neurodegenerative diseases. Chikusetsu saponin V (CsV), the most abundant member of saponins from Panax japonicus (SPJ), has attracted increasing attention for its potential to treat neurodegenerative diseases. However, the mechanisms are unclear. Our study intended to investigate the antioxidative effects of CsV in human neuroblastoma SH-SY5Y cells. Our data showed that CsV attenuated H2O2-induced cytotoxicity, inhibited ROS accumulation, increased the activities of superoxide dismutase (SOD) and GSH, and increased mitochondrial membrane potential dose-dependently. Further exploration of the mechanisms showed that CsV exhibited these effects through increasing the activation of oxidative-stress-associated factors including Sirt1, PGC-1α, and Mn-SOD. Moreover, CsV inhibited H2O2-induced down-regulation of Bcl-2 and up-regulation of Bax in a dose-dependent manner and, thus, increased the ratio of Bcl-2/Bax. In conclusion, our study demonstrated that CsV exhibited neuroprotective effects possibly through Sirt1/PGC-1α/Mn-SOD signaling pathways.

Download Full-text

PolyQ-expanded proteins impair cellular proteostasis of ataxin-3 through sequestering the co-chaperone HSJ1 into aggregates

Scientific Reports ◽

10.1038/s41598-021-87382-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hong-Wei Yue ◽

Jun-Ye Hong ◽

Shu-Xian Zhang ◽

Lei-Lei Jiang ◽

Hong-Yu Hu

Keyword(s):

Neurodegenerative Diseases ◽

Protein Misfolding ◽

Inclusion Bodies ◽

Protein Aggregates ◽

Proteasomal Degradation ◽

Dependent Manner ◽

Potential Mechanism ◽

Essential Factor ◽

Functional Loss ◽

Polyq Expansion

AbstractPolyglutamine (polyQ) expansion of proteins can trigger protein misfolding and amyloid-like aggregation, which thus lead to severe cytotoxicities and even the respective neurodegenerative diseases. However, why polyQ aggregation is toxic to cells is not fully elucidated. Here, we took the fragments of polyQ-expanded (PQE) ataxin-7 (Atx7) and huntingtin (Htt) as models to investigate the effect of polyQ aggregates on the cellular proteostasis of endogenous ataxin-3 (Atx3), a protein that frequently appears in diverse inclusion bodies. We found that PQE Atx7 and Htt impair the cellular proteostasis of Atx3 by reducing its soluble as well as total Atx3 level but enhancing formation of the aggregates. Expression of these polyQ proteins promotes proteasomal degradation of endogenous Atx3 and accumulation of its aggregated form. Then we verified that the co-chaperone HSJ1 is an essential factor that orchestrates the balance of cellular proteostasis of Atx3; and further discovered that the polyQ proteins can sequester HSJ1 into aggregates or inclusions in a UIM domain-dependent manner. Thereby, the impairment of Atx3 proteostasis may be attributed to the sequestration and functional loss of cellular HSJ1. This study deciphers a potential mechanism underlying how PQE protein triggers proteinopathies, and also provides additional evidence in supporting the hijacking hypothesis that sequestration of cellular interacting partners by protein aggregates leads to cytotoxicity or neurodegeneration.

Download Full-text

Genetic Variation in the Ontario Neurodegenerative Disease Research Initiative

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2019.228 ◽

2019 ◽

Vol 46 (5) ◽

pp. 491-498 ◽

Cited By ~ 2

Author(s):

Allison A. Dilliott ◽

Emily C. Evans ◽

Sali M.K. Farhan ◽

Mahdi Ghani ◽

Christine Sato ◽

...

Keyword(s):

Cognitive Impairment ◽

Neurodegenerative Diseases ◽

Neurodegenerative Disease ◽

Vascular Cognitive Impairment ◽

Phenotypic Analysis ◽

Disease Research ◽

Research Initiative ◽

E4 Allele ◽

Dose Dependent ◽

Lateral Sclerosis

ABSTRACT:Background/Objective:Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.Methods:Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.Results:Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.Conclusion:This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.

Download Full-text

Neuroprotective Effects of Geniposide in SH-SY5Y Cells and Primary Hippocampal Neurons Exposed to Aβ42

BioMed Research International ◽

10.1155/2014/284314 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 6

Author(s):

Ping Sun ◽

Haimin Ding ◽

Mi Liang ◽

Xiaojing Li ◽

Weichuan Mo ◽

...

Keyword(s):

Electron Microscope ◽

Cell Viability ◽

Hippocampal Neurons ◽

Dependent Manner ◽

Neuroprotective Effects ◽

Cellular Toxicity ◽

Sds Page ◽

Primary Hippocampal Neurons ◽

Main Component ◽

Dose Dependent

Our former studies have suggested that TongLuoJiuNao (TLJN) is clinically efficacious in the treatment of dementia and improving learning and memory in AD models. When Aβaggregated with oligomer, it is known to be able to induce cellular toxicity as well as cognitive impairment. We tested the possibility that TLJN affects the formation of Aβoligomers. In our experiment, TLJN improved cell viability, inhibited LDH release, and promoted the outgrowth of neurites of neurons treated with Aβ. Geniposide, the main component of TLJN, could increase the cell viability of SY5Y-APP695sw cells. The cytotoxicity of pretreated Aβwith geniposide was decreased in a dose-dependent manner. SDS-PAGE and Western blotting showed that geniposide and TLJN stimulated Aβoligomer assembly. Compared with the control, more and longer fibrils of Aβin the presence of geniposide were observed under electron microscope though the fibrils became less sensitive to thioflavin T staining. In sum, geniposide is able to protect neurons from Aβ-induced damage by remodeling Aβ.

Download Full-text