RBM45 associates with nuclear stress bodies and forms nuclear inclusions during chronic cellular stress and in neurodegenerative diseases

Chronic stress is a combination of nonspecific adaptive reactions of the body to the influence of various adverse stress factors which disrupt its homeostasis, and it is also a corresponding state of the organism’s nervous system (or the body in general). We hypothesized that chronic stress may be one of the causes occurence of several molecular and cellular types of stress. We analyzed literary sources and considered most of these types of stress in our review article. We examined genes and mutations of nuclear and mitochondrial genomes and also molecular variants which lead to various types of stress. The end result of chronic stress can be metabolic disturbance in humans and animals, leading to accumulation of reactive oxygen species (ROS), oxidative stress, energy deficiency in cells (due to a decrease in ATP synthesis) and mitochondrial dysfunction. These changes can last for the lifetime and lead to severe pathologies, including neurodegenerative diseases and atherosclerosis. The analysis of literature allowed us to conclude that under the influence of chronic stress, metabolism in the human body can be disrupted, mutations of the mitochondrial and nuclear genome and dysfunction of cells and their compartments can occur. As a result of these processes, oxidative, genotoxic, and cellular stress can occur. Therefore, chronic stress can be one of the causes forthe occurrence and development of neurodegenerative diseases and atherosclerosis. In particular, chronic stress can play a large role in the occurrence and development of oxidative, genotoxic, and cellular types of stress.

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Evidence of the Cellular Senescence Stress Response in Mitotically Active Brain Cells—Implications for Cancer and Neurodegeneration

Life ◽

10.3390/life11020153 ◽

2021 ◽

Vol 11 (2) ◽

pp. 153

Author(s):

Gregory J. Gillispie ◽

Eric Sah ◽

Sudarshan Krishnamurthy ◽

Mohamed Y. Ahmidouch ◽

Bin Zhang ◽

...

Keyword(s):

Stress Response ◽

Neurodegenerative Diseases ◽

Cell Fate ◽

Cellular Senescence ◽

Stress Responses ◽

Cellular Stress ◽

Surrounding Tissue ◽

Brain Cells ◽

Cell Fate Decisions ◽

The Brain

Cellular stress responses influence cell fate decisions. Apoptosis and proliferation represent opposing reactions to cellular stress or damage and may influence distinct health outcomes. Clinical and epidemiological studies consistently report inverse comorbidities between age-associated neurodegenerative diseases and cancer. This review discusses how one particular stress response, cellular senescence, may contribute to this inverse correlation. In mitotically competent cells, senescence is favorable over uncontrolled proliferation, i.e., cancer. However, senescent cells notoriously secrete deleterious molecules that drive disease, dysfunction and degeneration in surrounding tissue. In recent years, senescent cells have emerged as unexpected mediators of neurodegenerative diseases. The present review uses pre-defined criteria to evaluate evidence of cellular senescence in mitotically competent brain cells, highlights the discovery of novel molecular regulators and discusses how this single cell fate decision impacts cancer and degeneration in the brain. We also underscore methodological considerations required to appropriately evaluate the cellular senescence stress response in the brain.

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The Role of PERK in Understanding Development of Neurodegenerative Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22158146 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8146

Author(s):

Garrett Dalton Smedley ◽

Keenan E. Walker ◽

Shauna H. Yuan

Keyword(s):

Stress Response ◽

Protein Kinase ◽

Neurodegenerative Diseases ◽

Cellular Stress ◽

Cellular Stress Response ◽

Neural Cells ◽

Review Of The Literature ◽

Unfolded Protein ◽

Protein Response

Neurodegenerative diseases are an ever-increasing problem for the rapidly aging population. Despite this, our understanding of how these neurodegenerative diseases develop and progress, is in most cases, rudimentary. Protein kinase RNA (PKR)-like ER kinase (PERK) comprises one of three unfolded protein response pathways in which cells attempt to manage cellular stress. However, because of its role in the cellular stress response and the far-reaching implications of this pathway, error within the PERK pathway has been shown to lead to a variety of pathologies. Genetic and clinical studies show a correlation between failure of the PERK pathway in neural cells and the development of neurodegeneration, but the wide array of methodology of these studies is presenting conflicting narratives about the role of PERK in these affected systems. Because of the connection between PERK and pathology, PERK has become a high value target of study for understanding neurodegenerative diseases and potentially how to treat them. Here, we present a review of the literature indexed in PubMed of the PERK pathway and some of the complexities involved in investigating the protein’s role in the development of neurodegenerative diseases as well as how it may act as a target for therapeutics.

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CofActor: A light- and stress-gated optogenetic clustering tool to study disease-associated cytoskeletal dynamics in living cells

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.012427 ◽

2020 ◽

Vol 295 (32) ◽

pp. 11231-11245

Author(s):

Fatema B. Salem ◽

Wyatt P. Bunner ◽

Vishwanath V. Prabhu ◽

Abu-Bakarr Kuyateh ◽

Collin T. O'Bryant ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Reactive Oxygen Species ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Early Stage ◽

Cellular Stress ◽

Reactive Oxygen ◽

Atp Depletion ◽

Oxygen Species

The hallmarks of neurodegenerative diseases, including neural fibrils, reactive oxygen species, and cofilin–actin rods, present numerous challenges in the development of in vivo diagnostic tools. Biomarkers such as β-amyloid (Aβ) fibrils and Tau tangles in Alzheimer's disease are accessible only via invasive cerebrospinal fluid assays, and reactive oxygen species can be fleeting and challenging to monitor in vivo. Although remaining a challenge for in vivo detection, the protein–protein interactions underlying these disease-specific biomarkers present opportunities for the engineering of in vitro pathology-sensitive biosensors. These tools can be useful for investigating early stage events in neurodegenerative diseases in both cellular and animal models and may lead to clinically useful reagents. Here, we report a light- and cellular stress–gated protein switch based on cofilin–actin rod formation, occurring in stressed neurons in the Alzheimer's disease brain and following ischemia. By coupling the stress-sensitive cofilin–actin interaction with the light-responsive Cry2-CIB blue-light switch, referred to hereafter as the CofActor, we accomplished both light- and energetic/oxidative stress–gated control of this interaction. Site-directed mutagenesis of both cofilin and actin revealed residues critical for sustaining or abrogating the light- and stress-gated response. Of note, the switch response varied depending on whether cellular stress was generated via glycolytic inhibition or by both glycolytic inhibition and azide-induced ATP depletion. We also demonstrate light- and cellular stress–gated switch function in cultured hippocampal neurons. CofActor holds promise for the tracking of early stage events in neurodegeneration and for investigating actin's interactions with other proteins during cellular stress.

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RBM45 associates with nuclear stress bodies and forms nuclear inclusions during chronic cellular stress and in neurodegenerative diseases

10.1101/856880 ◽

2019 ◽

Author(s):

Mahlon Collins ◽

Yang Li ◽

Robert Bowser

Keyword(s):

Rna Binding ◽

Cellular Stress ◽

Heat Shock Factor 1 ◽

Nuclear Inclusions ◽

Nuclear Inclusion ◽

Cell Type ◽

Nuclear Speckles ◽

Cytoplasmic Inclusions ◽

Inclusion Formation ◽

Self Association

AbstractRBM45 is a multifunctional RNA binding protein (RBP) found in cytoplasmic and nuclear inclusions in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Alzheimer’s disease (AD). While cytoplasmic RBM45 inclusions contain other disease-associated proteins, nuclear RBM45 inclusions are morphologically and biochemically distinct from previously described nuclear inclusion pathology in these diseases. To better understand nuclear RBM45 aggregation and inclusion formation, we evaluated the association of RBM45 with a variety of membraneless nuclear organelles, including nuclear speckles, Cajal bodies, and nuclear gems. Under basal conditions, RBM45 is diffusely distributed throughout the nucleus and does not localize to a specific nuclear organelle. During cellular stress, however, the nuclear RBM45 distribution undergoes an RNA-binding dependent rearrangement wherein RBM45 coalesces into a small number of nuclear puncta. These puncta contain the nuclear stress body (NSB) markers heat shock factor 1 (HSF1) and scaffold attachment factor B (SAFB). During chronic stress, the persistent association of RBM45 with NSBs leads to the formation of large, insoluble nuclear RBM45 inclusions. RBM45 nuclear inclusions persist after stressor removal and NSB disassembly and the inclusions resemble the nuclear RBM45 pathology seen in ALS, FTLD, and AD. We also quantified the cell type- and disease-specific patterns of RBM45 pathology in ALS, FTLD, AD, and non-neurologic disease control subjects. RBM45 nuclear and cytoplasmic inclusions are found in neurons and glia in ALS, FTLD, and AD but not in controls. Across diseases, RBM45 nuclear inclusion pathology occurs more frequently than cytoplasmic RBM45 inclusion pathology and exhibits cell type-specific variation. Collectively, our results define new stress-associated functions of RBM45, a mechanism for its nuclear aggregation and inclusion formation, a role for NSBs in the pathogenesis of diseases such as ALS, FTLD, and AD, and further underscore the importance of self-association to both the normal and pathological functions of RBPs in these diseases.

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Staufen blocks autophagy in neurodegeneration

10.1101/659649 ◽

2019 ◽

Cited By ~ 1

Author(s):

Sharan Paul ◽

Warunee Dansithong ◽

Mandi Gandelman ◽

Tao Zu ◽

Laura P.W. Ranum ◽

...

Keyword(s):

Animal Models ◽

Neurodegenerative Diseases ◽

Neurodegenerative Disorder ◽

Cellular Stress ◽

Cellular Stress Response ◽

Autophagic Flux ◽

Dividing Cells ◽

Novel Target ◽

Cellular Components ◽

In Cells

AbstractResponse to cellular stress represents a highly conserved pathway in evolution. Cells respond to stress with modified synthesis of new proteins by the formation of stress granules (SGs), inhibition of translation initiation and by increased recycling of cellular components through autophagy. One of the master regulators of this response is the mechanistic target of rapamycin (mTOR) kinase1,2. We recently reported that Staufen1 (STAU1), a stress granule protein, was overabundant in the rare neurodegenerative disorder SCA2 and provided a link between SG formation and autophagy3. In cells harboring mutant ATXN2, STAU1 could also be increased by bafilomycin A consistent with impaired autophagosome lysosome fusion3. Here we now examine this association and show the molecular mechanism leading to autophagic block in cells with microtubule associated protein tau (MAPT), presenilin 1 (PSEN1), huntingtin (HTT), TAR DNA-binding protein-43 gene (TARDBP) or C9orf72-SMCR8 complex subunit (C9orf72) mutations underlying a great number of neurodegenerative diseases4–8. We found that STAU1 overabundance was present in all cell lines and animal models tested, that it was post-translational, and that it was associated with an increase in phosphorylated mTOR (P-mTOR) and autophagic block. Exogenous expression of STAU1 in wild-type cells was sufficient to reduce autophagic flux by itself. Mechanistically, STAU1 directly interacted with the mTOR-5’UTR and enhanced mTOR translation. As STAU1 itself is degraded by autophagy, this interaction and the resulting autophagic block results in a maladaptive amplifying response to chronic stress. Targeting STAU1 by RNAi decreased mTOR hyperactivity and normalized mTOR downstream targets in dividing cells, post-mitotic neurons and animal models of SCA2 and ALS-TDP-43 or C9orf72 associated neurodegeneration. In summary, STAU1 is necessary and sufficient to mediate a maladaptive cellular stress response and is a novel target for RNAi-mediated treatment of neurodegenerative diseases.

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14-3-3 Proteins Are on the Crossroads of Cancer, Aging, and Age-Related Neurodegenerative Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20143518 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3518 ◽

Cited By ~ 10

Author(s):

Xiaolan Fan ◽

Lang Cui ◽

Yao Zeng ◽

Wenhao Song ◽

Uma Gaur ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Neurodegenerative Disease ◽

Molecular Chaperones ◽

Cellular Stress ◽

Expression Patterns ◽

Eukaryotic Cells ◽

Unfolded Proteins ◽

Substantial Role ◽

Similar Expression ◽

Age Related

14-3-3 proteins are a family of conserved regulatory adaptor molecules which are expressed in all eukaryotic cells. These proteins participate in a variety of intracellular processes by recognizing specific phosphorylation motifs and interacting with hundreds of target proteins. Also, 14-3-3 proteins act as molecular chaperones, preventing the aggregation of unfolded proteins under conditions of cellular stress. Furthermore, 14-3-3 proteins have been shown to have similar expression patterns in tumors, aging, and neurodegenerative diseases. Therefore, we put forward the idea that the adaptor activity and chaperone-like activity of 14-3-3 proteins might play a substantial role in the above-mentioned conditions. Interestingly, 14-3-3 proteins are considered to be standing at the crossroads of cancer, aging, and age-related neurodegenerative diseases. There are great possibilities to improve the above-mentioned diseases and conditions through intervention in the activity of the 14-3-3 protein family.

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Accumulation of the sigma-1 receptor is common to neuronal nuclear inclusions in various neurodegenerative diseases

Neuropathology ◽

10.1111/neup.12080 ◽

2013 ◽

Vol 34 (2) ◽

pp. 148-158 ◽

Cited By ~ 38

Author(s):

Yasuo Miki ◽

Fumiaki Mori ◽

Tomoya Kon ◽

Kunikazu Tanji ◽

Yasuko Toyoshima ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Nuclear Inclusions ◽

Sigma 1 Receptor ◽

Sigma 1

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Cytoplasmic Invaginations in Trophoblasts and Epithelial Cells of Rat

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010006667x ◽

1971 ◽

Vol 29 ◽

pp. 524-525

Author(s):

Iracema M. Baccarini

Keyword(s):

Osmium Tetroxide ◽

Uranyl Acetate ◽

Nuclear Inclusions ◽

Mucous Cells ◽

Electron Microscopic ◽

Cervical Epithelium ◽

Intact Membrane ◽

Microscopic Studies ◽

Abnormal Cells ◽

Nuclear Features

Some morphological nuclear features (invaginations) in normal and abnormal cells have been described in several electron microscopic studies. They have been referred to by others as blebs, loops, pockets, sheets, bodies, nuclear inclusions and cytoplasmic invaginations. Identical appearing structures were found in cells of the uterine cervical epithelium, in trophoblasts of blastocysts and in trophoblasts of rat placenta.Methods. Uterine cervix (normal rats), rat placenta (9-10 days gestation) and blastocyst were placed in 3% glutarahdehyde for 3 hours. The tissue was washed in phosphate buffer for 24 hours, postfixed in 1%. buffered osmium tetroxide for 1-2 hours and embedded in epon araldite. Sections were double stained with uranyl acetate and lead citrate and viewed in E. M. Siemens 200.Observations. Nuclear invaginations were found in basal, parabasal and mucous cells of the cervix epithelium, in trophoblasts of blastocyst and in trophoblasts of placenta. An oval, round or elongated invagination contained heterogenously cytoplasm surrounded by a double intact membrane; usually several invaginations were found in the same nucleus.

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Autophagy and ageing: implications for age-related neurodegenerative diseases

Essays in Biochemistry ◽

10.1042/bse0550119 ◽

2013 ◽

Vol 55 ◽

pp. 119-131 ◽

Cited By ~ 37

Author(s):

Bernadette Carroll ◽

Graeme Hewitt ◽

Viktor I. Korolchuk

Keyword(s):

Neurodegenerative Diseases ◽

Energy Availability ◽

Future Studies ◽

Intracellular Degradation ◽

Age Related ◽

Autophagy Induction ◽

Social Importance ◽

Cellular Dysfunction ◽

Autophagy Activity ◽

Intense Research

Autophagy is a process of lysosome-dependent intracellular degradation that participates in the liberation of resources including amino acids and energy to maintain homoeostasis. Autophagy is particularly important in stress conditions such as nutrient starvation and any perturbation in the ability of the cell to activate or regulate autophagy can lead to cellular dysfunction and disease. An area of intense research interest is the role and indeed the fate of autophagy during cellular and organismal ageing. Age-related disorders are associated with increased cellular stress and assault including DNA damage, reduced energy availability, protein aggregation and accumulation of damaged organelles. A reduction in autophagy activity has been observed in a number of ageing models and its up-regulation via pharmacological and genetic methods can alleviate age-related pathologies. In particular, autophagy induction can enhance clearance of toxic intracellular waste associated with neurodegenerative diseases and has been comprehensively demonstrated to improve lifespan in yeast, worms, flies, rodents and primates. The situation, however, has been complicated by the identification that autophagy up-regulation can also occur during ageing. Indeed, in certain situations, reduced autophagosome induction may actually provide benefits to ageing cells. Future studies will undoubtedly improve our understanding of exactly how the multiple signals that are integrated to control appropriate autophagy activity change during ageing, what affect this has on autophagy and to what extent autophagy contributes to age-associated pathologies. Identification of mechanisms that influence a healthy lifespan is of economic, medical and social importance in our ‘ageing’ world.

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