bims-proarb 2021-10-24 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2021–10–24
twenty-one papers selected by
Rich Giadone, Harvard University

Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases.
Proteostasis deregulation as a driver of C9ORF72 pathogenesis.
The Hsp70-Hsp90 go-between Hop/Stip1/Sti1 is a proteostatic switch and may be a drug target in cancer and neurodegeneration.
Sharing is caring: The benefits of distributing protein aggregates among microglial networks.
Aggregation and structure of amyloid β-protein.
eIF2A-knockout mice reveal decreased life span and metabolic syndrome.
The effects of agomelatine on endoplasmic reticulum stress related to mitochondrial dysfunction in hippocampus of aging rat model.
Extracellular vesicle-associated small heat shock proteins as therapeutic agents in neurodegenerative diseases and beyond.
Pharmacological Inhibition of Inositol-Requiring Enzyme 1α RNase Activity Protects Pancreatic Beta Cell and Improves Diabetic Condition in Insulin Mutation-Induced Diabetes.
The penalty of stress - epichaperomes negatively reshaping the brain in neurodegenerative disorders.
Mitochondrial Dysfunction, Protein Misfolding and Neuroinflammation in Parkinson's Disease: Roads to Biomarker Discovery.
Hsp22 Deficiency Induces Age-Dependent Cardiac Dilation and Dysfunction by Impairing Autophagy, Metabolism, and Oxidative Response.
The Amyloid Fibril-Forming β-Sheet Regions of Amyloid β and α-Synuclein Preferentially Interact with the Molecular Chaperone 14-3-3ζ.
Are stress granules the RNA analogs of misfolded protein aggregates?
Selective activation of cannabinoid receptor-2 reduces white matter injury via PERK signaling in a rat model of traumatic brain injury.
Anti-PrP monoclonal antibody as a novel treatment for neurogenesis in mouse model of Alzheimer's disease.
Dynamic remodeling of ribosomes and endoplasmic reticulum in axon terminals of motoneurons.
Short-Term Sleep Fragmentation Dysregulates Autophagy in a Brain Region-Specific Manner.
Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases.
Tau Post-Translational Modifications: Potentiators of Selective Vulnerability in Sporadic Alzheimer's Disease.
Can we make drug discovery targeting fundamental mechanisms of aging a reality?

Cells. 2021 Sep 29. pii: 2596. [Epub ahead of print]10(10):

Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases.

Lisha Wang, Liza Bergkvist, Rajnish Kumar, Bengt Winblad, Pavel F Pavlov.

  The dysfunction of the proteostasis network is a molecular hallmark of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Molecular chaperones are a major component of the proteostasis network and maintain cellular homeostasis by folding client proteins, assisting with intracellular transport, and interfering with protein aggregation or degradation. Heat shock protein 70 kDa (Hsp70) and 90 kDa (Hsp90) are two of the most important chaperones whose functions are dependent on ATP hydrolysis and collaboration with their co-chaperones. Numerous studies implicate Hsp70, Hsp90, and their co-chaperones in neurodegenerative diseases. Targeting the specific protein-protein interactions between chaperones and their particular partner co-chaperones with small molecules provides an opportunity to specifically modulate Hsp70 or Hsp90 function for neurodegenerative diseases. Here, we review the roles of co-chaperones in Hsp70 or Hsp90 chaperone cycles, the impacts of co-chaperones in neurodegenerative diseases, and the development of small molecules modulating chaperone/co-chaperone interactions. We also provide a future perspective of drug development targeting chaperone/co-chaperone interactions for neurodegenerative diseases.

Keywords:  Hsp70; Hsp90; co-chaperones; neurodegenerative diseases; small molecules

DOI:  https://doi.org/10.3390/cells10102596
J Neurochem. 2021 Oct 22.

Proteostasis deregulation as a driver of C9ORF72 pathogenesis.

Paulina Torres, Felipe Cabral-Miranda, Vicente Gonzalez-Teuber, Claudio Hetz.

  Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative disorders that display overlapping features. The hexanucleotide repeat expansion GGGGCC (G4 C2 ) in C9ORF72 gene has been causally linked to both ALS and FTD emergence, thus opening a novel potential therapeutic target for disease intervention. A main driver of C9ORF72 pathology is the disruption of distinct cellular processes involved in the function of the proteostasis network. Here we discuss main findings relating the induction of neurodegeneration by C9ORF72 mutation and proteostasis deregulation, highlighting the role of the endoplasmic reticulum stress, nuclear transport, and autophagy in the disease process. We further discuss possible points of intervention to target proteostasis mediators to treat C9ORF72-linked ALS/FTD.

Keywords:  ALS; C9ORF72; ER stress; FTD; ISR; UPR; proteostasis

DOI:  https://doi.org/10.1111/jnc.15529
Cell Mol Life Sci. 2021 Oct 22.

The Hsp70-Hsp90 go-between Hop/Stip1/Sti1 is a proteostatic switch and may be a drug target in cancer and neurodegeneration.

Kaushik Bhattacharya, Didier Picard.

  The Hsp70 and Hsp90 molecular chaperone systems are critical regulators of protein homeostasis (proteostasis) in eukaryotes under normal and stressed conditions. The Hsp70 and Hsp90 systems physically and functionally interact to ensure cellular proteostasis. Co-chaperones interact with Hsp70 and Hsp90 to regulate and to promote their molecular chaperone functions. Mammalian Hop, also called Stip1, and its budding yeast ortholog Sti1 are eukaryote-specific co-chaperones, which have been thought to be essential for substrate ("client") transfer from Hsp70 to Hsp90. Substrate transfer is facilitated by the ability of Hop to interact simultaneously with Hsp70 and Hsp90 as part of a ternary complex. Intriguingly, in prokaryotes, which lack a Hop ortholog, the Hsp70 and Hsp90 orthologs interact directly. Recent evidence shows that eukaryotic Hsp70 and Hsp90 can also form a prokaryote-like binary chaperone complex in the absence of Hop, and that this binary complex displays enhanced protein folding and anti-aggregation activities. The canonical Hsp70-Hop-Hsp90 ternary chaperone complex is essential for optimal maturation and stability of a small subset of clients, including the glucocorticoid receptor, the tyrosine kinase v-Src, and the 26S/30S proteasome. Whereas many cancers have increased levels of Hop, the levels of Hop decrease in the aging human brain. Since Hop is not essential in all eukaryotic cells and organisms, tuning Hop levels or activity might be beneficial for the treatment of cancer and neurodegeneration.

Keywords:  Aggregation; Aging; Degradation; Molecular chaperone; Proteasome; Protein folding; Proteostasis; Stress response

DOI:  https://doi.org/10.1007/s00018-021-03962-z
Neuron. 2021 Oct 20. pii: S0896-6273(21)00776-5. [Epub ahead of print]109(20): 3228-3230

Sharing is caring: The benefits of distributing protein aggregates among microglial networks.

Vera I Wiersma, Magdalini Polymenidou.

  The trafficking of protein aggregates through neural circuitries causes adverse outcomes, including propagation of pathology and toxicity in neurodegenerative diseases. In a recent issue of Cell, Scheiblich et al. (2021) describe an advantageous aggregate-sharing strategy in microglial networks that nurtures α-synuclein-loaded members back to health.

Keywords:  microglia; mitochondria; neurodegenerative disorders; prion-like spreading; protein aggregation; α-synuclein

DOI:  https://doi.org/10.1016/j.neuron.2021.10.008
Neurochem Int. 2021 Oct 13. pii: S0197-0186(21)00254-0. [Epub ahead of print]151 105208

Aggregation and structure of amyloid β-protein.

Kenjiro Ono, Takahiro Watanabe-Nakayama.

  Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder and is characterized by major pathological hallmarks in the brain, including plaques composed of amyloid β-protein (Aβ) and neurofibrillary tangles of tau protein. Genetic studies, biochemical data, and animal models have suggested that Aβ is a critical species in the pathogenesis of AD. Aβ molecules aggregate to form oligomers, protofibrils (PFs), and mature fibrils. Because of their instability and structural heterogeneity, the misfolding and aggregation of Aβ is a highly complex process, leading to a variety of aggregates with different structures and morphologies. However, the elucidation of Aβ molecules is essential because they are believed to play an important role in AD pathogenesis. Recent combination studies using nuclear magnetic resonance (NMR) and cryo-electron microscopy (cryo-EM) have primarily revealed more detailed information about their aggregation process, including fibril extension and secondary nucleation, and the structural polymorphism of the fibrils under a variety of some conditions, including the actual brain. This review attempts to summarize the existing information on the major properties of the structure and aggregation of Aβ.

Keywords:  Aggregation; Alzheimer's disease; Amyloid β-protein (Aβ); Secondary nucleation; Structure

DOI:  https://doi.org/10.1016/j.neuint.2021.105208
FASEB J. 2021 Nov;35(11): e21990

eIF2A-knockout mice reveal decreased life span and metabolic syndrome.

Richard Anderson, Anchal Agarwal, Arnab Ghosh, Bo-Jhih Guan, Jackson Casteel, Nina Dvorina, William M Baldwin, Barsanjit Mazumder, Taras Y Nazarko, William C Merrick, David A Buchner, Maria Hatzoglou, Roman V Kondratov, Anton A Komar.

  Eukaryotic initiation factor 2A (eIF2A) is a 65 kDa protein that functions in minor initiation pathways, which affect the translation of only a subset of messenger ribonucleic acid (mRNAs), such as internal ribosome entry site (IRES)-containing mRNAs and/or mRNAs harboring upstream near cognate/non-AUG start codons. These non-canonical initiation events are important for regulation of protein synthesis during cellular development and/or the integrated stress response. Selective eIF2A knockdown in cellular systems significantly inhibits translation of such mRNAs, which rely on alternative initiation mechanisms for their translation. However, there exists a gap in our understanding of how eIF2A functions in mammalian systems in vivo (on the organismal level) and ex vivo (in cells). Here, using an eIF2A-knockout (KO) mouse model, we present evidence implicating eIF2A in the biology of aging, metabolic syndrome and central tolerance. We discovered that eIF2A-KO mice have reduced life span and that eIF2A plays an important role in maintenance of lipid homeostasis, the control of glucose tolerance, insulin resistance and also reduces the abundance of B lymphocytes and dendritic cells in the thymic medulla of mice. We also show the eIF2A KO affects male and female mice differently, suggesting that eIF2A may affect sex-specific pathways. Interestingly, our experiments involving pharmacological induction of endoplasmic reticulum (ER) stress with tunicamycin did not reveal any substantial difference between the response to ER stress in eIF2A-KO and wild-type mice. The identification of eIF2A function in the development of metabolic syndrome bears promise for the further identification of specific eIF2A targets responsible for these changes.

Keywords:  ER stress; eukaryotic initiation factor 2A (eIF2A); life span; lipid homeostasis; metabolic syndrome

DOI:  https://doi.org/10.1096/fj.202101105R
Chem Biol Interact. 2021 Oct 18. pii: S0009-2797(21)00341-0. [Epub ahead of print] 109703

The effects of agomelatine on endoplasmic reticulum stress related to mitochondrial dysfunction in hippocampus of aging rat model.

Teera Chanmanee, Jittiporn Wongpun, Chainarong Tocharus, Piyarat Govitrapong, Jiraporn Tocharus.

   BACKGROUND: Agomelatine, a novel antidepressant, is a melatonin MT receptor agonist and serotonin 5HT2C receptor antagonist. In this study, agomelatine was used to investigate the molecular mechanisms of hippocampal aging associated with endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and apoptosis, all of which led to short-term memory impairment.
METHOD: Hippocampal aging was induced in male Wistar rats by d-galactose (D-gal) intraperitoneal injection (100 mg/kg) for 14 weeks. During the last 4 weeks of D-gal treatment, rats were treated with agomelatine (40 mg/kg) or melatonin (10 mg/kg). At the end of the experiment, all rats were assessed for short-term memory by using the Morris water maze test. Subsequently, rats were sacrified and the hippocampus was removed from each rat for determination of reactive oxygen species (ROS), malondialdehyde (MDA), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays; and immunohistochemistry related to ER stress, mitochondrial dysfunction, and apoptosis.
RESULTS: Agomelatine suppressed the expression of the aging-related proteins P16 and receptor for advanced glycation endproducts (RAGE), the expression of NADPH oxidase (NOX) 2 and 4, and ROS production. This treatment also shifted the morphology of astrocytes and microglia toward homeostasis. Furthermore, agomelatine decreased inositol-requiring enzyme 1 (pIRE1), protein kinase R-like endoplasmic reticulum kinase (pPERK), and chaperone binding immunoglobulin protein (BiP), leading to suppression of ER stress markers C/EBP homologous protein (CHOP) and caspase-12. Agomelatine reduced Ca2+ from the ER and stabilized the mitochondrial membrane stability, which was denoted by the BCL2 Associated X (Bax)/B-cell lymphoma 2 (Bcl2) balance. Agomelatine decreased cleaved caspase-3 production and the Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL)-positive area, and glutamate excitotoxicity was prevented via suppression of N-methyl-d-aspartate (NMDA) receptor subunit expression. Agomelatine exhibited effects that were similar to melatonin.
CONCLUSION: Agomelatine improved neurodegeneration in a rat model of hippocampal aging by attenuating ROS production, ER stress, mitochondrial dysfunction, excitotoxicity, and apoptosis.

Keywords:  Agomelatine; ER stress; Hippocampal aging; Melatonin; d-galactose

DOI:  https://doi.org/10.1016/j.cbi.2021.109703
Adv Drug Deliv Rev. 2021 Oct 18. pii: S0169-409X(21)00402-6. [Epub ahead of print] 114009

Extracellular vesicle-associated small heat shock proteins as therapeutic agents in neurodegenerative diseases and beyond.

Bram Van den Broek, Charlotte Wuyts, Joy Irobi.

  Increasing evidence points towards using extracellular vesicles (EVs) as a therapeutic strategy in neurodegenerative diseases such as multiple sclerosis, Parkinson's, and Alzheimer's disease. EVs are nanosized carriers that play an essential role in intercellular communication and cellular homeostasis by transporting an active molecular cargo, including a large variety of proteins. Recent publications demonstrate that small heat shock proteins (HSPBs) exhibit a beneficial role in neurodegenerative diseases. Moreover, it is defined that HSPBs target the autophagy and the apoptosis pathway, playing a prominent role in chaperone activity and cell survival. This review elaborates on the therapeutic potential of EVs and HSPBs, in particular HSPB1 and HSPB8, in neurodegenerative diseases. We conclude that EVs and HSPBs positively influence neuroinflammation, central nervous system (CNS) repair, and protein aggregation in CNS disorders. Moreover, we propose the use of HSPB-loaded EVs as advanced nanocarriers for the future development of neurodegenerative disease therapies.

Keywords:  CNS disorders; Extracellular vesicles; molecular chaperones; neurodegeneration; neuroprotection; small heat shock proteins

DOI:  https://doi.org/10.1016/j.addr.2021.114009
Front Endocrinol (Lausanne). 2021 ;12 749879

Pharmacological Inhibition of Inositol-Requiring Enzyme 1α RNase Activity Protects Pancreatic Beta Cell and Improves Diabetic Condition in Insulin Mutation-Induced Diabetes.

Oana Herlea-Pana, Venkateswararao Eeda, Ram Babu Undi, Hui-Ying Lim, Weidong Wang.

  β-cell ER stress plays an important role in β-cell dysfunction and death during the pathogenesis of diabetes. Proinsulin misfolding is regarded as one of the primary initiating factors of ER stress and unfolded protein response (UPR) activation in β-cells. Here, we found that the ER stress sensor inositol-requiring enzyme 1α (IRE1α) was activated in the Akita mice, a mouse model of mutant insulin gene-induced diabetes of youth (MIDY), a monogenic diabetes. Normalization of IRE1α RNase hyperactivity by pharmacological inhibitors significantly ameliorated the hyperglycemic conditions and increased serum insulin levels in Akita mice. These benefits were accompanied by a concomitant protection of functional β-cell mass, as shown by the suppression of β-cell apoptosis, increase in mature insulin production and reduction of proinsulin level. At the molecular level, we observed that the expression of genes associated with β-cell identity and function was significantly up-regulated and ER stress and its associated inflammation and oxidative stress were suppressed in islets from Akita mice treated with IRE1α RNase inhibitors. This study provides the evidence of the in vivo efficacy of IRE1α RNase inhibitors in Akita mice, pointing to the possibility of targeting IRE1α RNase as a therapeutic direction for the treatment of diabetes.

Keywords:  Beta cell failure; ER stress; Ire1alpha; Ire1alpha inhibition; beta cell protection; monogenic diabetes; proinsulin misfolding; unfolded protein response

DOI:  https://doi.org/10.3389/fendo.2021.749879
J Neurochem. 2021 Oct 17.

The penalty of stress - epichaperomes negatively reshaping the brain in neurodegenerative disorders.

Stephen D Ginsberg, Suhasini Joshi, Sahil Sharma, Gianny Guzman, Tai Wang, Ottavio Arancio, Gabriela Chiosis.

  Adaptation to acute and chronic stress and/or persistent stressors is a subject of wide interest in central nervous system disorders. In this context, stress is an effector of change in organismal homeostasis and the response is generated when the brain perceives a potential threat. Herein, we discuss a nuanced and granular view whereby a wide variety of genotoxic and environmental stressors, including aging, genetic risk factors, environmental exposures, and age- and lifestyle-related changes, act as direct insults to cellular, as opposed to organismal, homeostasis. These two concepts of how stressors impact the central nervous system are not mutually exclusive. We discuss how maladaptive stressor-induced changes in protein connectivity through epichaperomes, disease-associated pathologic scaffolds composed of tightly bound chaperones, co-chaperones, and other factors, impact intracellular protein functionality altering phenotypes, that in turn disrupt and remodel brain networks ranging from intercellular to brain connectome levels. We provide an evidence-based view how these maladaptive changes ranging from stressor to phenotype provide unique precision medicine opportunities for diagnostic and therapeutic development, especially in the context of neurodegenerative disorders including Alzheimer's disease where treatment options are currently limited.

Keywords:  Alzheimer’s disease; Stressor-to-phenotype; chronic stress and stressors; epichaperomes; maladaptive response to stress; synaptic plasticity

DOI:  https://doi.org/10.1111/jnc.15525
Biomolecules. 2021 Oct 13. pii: 1508. [Epub ahead of print]11(10):

Mitochondrial Dysfunction, Protein Misfolding and Neuroinflammation in Parkinson's Disease: Roads to Biomarker Discovery.

Anna Picca, Flora Guerra, Riccardo Calvani, Roberta Romano, Hélio José Coelho-Júnior, Cecilia Bucci, Emanuele Marzetti.

  Parkinson's Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational modifications, such as α-syn phosphorylation, have been identified among the multiple factors supporting α-syn accrual during PD. A decline in the clearance capacity of the ubiquitin-proteasome and the autophagy-lysosomal systems, together with mitochondrial dysfunction, have been indicated as major pathophysiological mechanisms of PD neurodegeneration. The accrual of misfolded α-syn aggregates into soluble oligomers, and the generation of insoluble fibrils composing the core of intraneuronal Lewy bodies and Lewy neurites observed during PD neurodegeneration, are ignited by the overproduction of reactive oxygen species (ROS). The ROS activate the α-syn aggregation cascade and, together with the Lewy bodies, promote neurodegeneration. However, the molecular pathways underlying the dynamic evolution of PD remain undeciphered. These gaps in knowledge, together with the clinical heterogeneity of PD, have hampered the identification of the biomarkers that may be used to assist in diagnosis, treatment monitoring, and prognostication. Herein, we illustrate the main pathways involved in PD pathogenesis and discuss their possible exploitation for biomarker discovery.

Keywords:  DAMPs; alpha-synuclein; beta-amyloid (Aβ); cytokine; extracellular vesicles; inflammation; mitochondrial-derived vesicles; mitophagy; neurofilaments light chain (NfL); p-tau pathology

DOI:  https://doi.org/10.3390/biom11101508
Antioxidants (Basel). 2021 Sep 29. pii: 1550. [Epub ahead of print]10(10):

Hsp22 Deficiency Induces Age-Dependent Cardiac Dilation and Dysfunction by Impairing Autophagy, Metabolism, and Oxidative Response.

Wenqian Wu, Xiaonan Sun, Xiaomeng Shi, Lo Lai, Charles Wang, Mingxin Xie, Gangjian Qin, Hongyu Qiu.

  Heat shock protein 22 (Hsp22) is a small heat shock protein predominantly expressed in skeletal and cardiac muscle. Previous studies indicate that Hsp22 plays a vital role in protecting the heart against cardiac stress. However, the essential role of Hsp22 in the heart under physiological conditions remains largely unknown. In this study, we used an Hsp22 knockout (KO) mouse model to determine whether loss of Hsp22 impairs cardiac growth and function with increasing age under physiological conditions. Cardiac structural and functional alterations at baseline were measured using echocardiography and invasive catheterization in Hsp22 KO mice during aging transition compared to their age-matched wild-type (WT) littermates. Our results showed that Hsp22 deletion induced progressive cardiac dilation along with declined function during the aging transition. Mechanistically, the loss of Hsp22 impaired BCL-2-associated athanogene 3 (BAG3) expression and its associated cardiac autophagy, undermined cardiac energy metabolism homeostasis and increased oxidative damage. This study showed that Hsp22 played an essential role in the non-stressed heart during the early stage of aging, which may bring new insight into understanding the pathogenesis of age-related dilated cardiomyopathy.

Keywords:  Hsp22; autophagy; cardiac dysfunction; cardiomyopathy; metabolism; oxidative stress

DOI:  https://doi.org/10.3390/antiox10101550
Molecules. 2021 Oct 11. pii: 6120. [Epub ahead of print]26(20):

The Amyloid Fibril-Forming β-Sheet Regions of Amyloid β and α-Synuclein Preferentially Interact with the Molecular Chaperone 14-3-3ζ.

Danielle M Williams, David C Thorn, Christopher M Dobson, Sarah Meehan, Sophie E Jackson, Joanna M Woodcock, John A Carver.

  14-3-3 proteins are abundant, intramolecular proteins that play a pivotal role in cellular signal transduction by interacting with phosphorylated ligands. In addition, they are molecular chaperones that prevent protein unfolding and aggregation under cellular stress conditions in a similar manner to the unrelated small heat-shock proteins. In vivo, amyloid β (Aβ) and α-synuclein (α-syn) form amyloid fibrils in Alzheimer's and Parkinson's diseases, respectively, a process that is intimately linked to the diseases' progression. The 14-3-3ζ isoform potently inhibited in vitro fibril formation of the 40-amino acid form of Aβ (Aβ40) but had little effect on α-syn aggregation. Solution-phase NMR spectroscopy of 15N-labeled Aβ40 and A53T α-syn determined that unlabeled 14-3-3ζ interacted preferentially with hydrophobic regions of Aβ40 (L11-H21 and G29-V40) and α-syn (V3-K10 and V40-K60). In both proteins, these regions adopt β-strands within the core of the amyloid fibrils prepared in vitro as well as those isolated from the inclusions of diseased individuals. The interaction with 14-3-3ζ is transient and occurs at the early stages of the fibrillar aggregation pathway to maintain the native, monomeric, and unfolded structure of Aβ40 and α-syn. The N-terminal regions of α-syn interacting with 14-3-3ζ correspond with those that interact with other molecular chaperones as monitored by in-cell NMR spectroscopy.

Keywords:  14-3-3 proteins; NMR spectroscopy; amyloid fibril; amyloid β; molecular chaperone; α-synuclein

DOI:  https://doi.org/10.3390/molecules26206120
RNA. 2021 Oct 20. pii: rna.079000.121. [Epub ahead of print]

Are stress granules the RNA analogs of misfolded protein aggregates?

Nina Ripin, Roy Parker.

  RNP granules are ubiquitous features of eukaryotic cells. Several observations argue that the formation of at least some RNP granules can be considered analogous to the formation of unfolded protein aggregates. First, unfolded protein aggregates form from the exposure of promiscuous protein interaction surfaces, while some mRNP granules form, at least in part, by promiscuous intermolecular RNA-RNA interactions due to exposed RNA surfaces when mRNAs are not engaged with ribosomes. Second, analogous to the role of protein chaperones in preventing misfolded protein aggregation, cells contain abundant "RNA chaperones" to limit inappropriate RNA-RNA interactions and prevent mRNP granule formation. Third, analogous to the role of protein aggregates in diseases, situations where RNA aggregation exceeds the capacity of RNA chaperones to disaggregate RNAs may contribute to human disease. Understanding that RNP granules can be considered as promiscuous, reversible RNA aggregation events allows insight into their composition and how cells have evolved functions for RNP granules.

Keywords:  RNA aggregates; RNA chaperones; eIF4A; stress granules

DOI:  https://doi.org/10.1261/rna.079000.121
Exp Neurol. 2021 Oct 19. pii: S0014-4886(21)00307-1. [Epub ahead of print] 113899

Selective activation of cannabinoid receptor-2 reduces white matter injury via PERK signaling in a rat model of traumatic brain injury.

Lin Li, Qing Luo, Bin Shang, Xiaomin Yang, Yuan Zhang, Qiuling Pan, Na Wu, Wei Tang, Donglin Du, Xiaochuan Sun, Li Jiang.

   BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) destroys white matter, and this destruction is aggravated by secondary neuroinflammatory reactions. Although white matter injury (WMI) is strongly correlated with poor neurological function, understanding of white matter integrity maintenance is limited, and no available therapies can effectively protect white matter. One candidate approach that may fulfill this goal is cannabinoid receptor 2 (CB2) agonist treatment. Here, we confirmed that a selective CB2 agonist, JWH133, protected white matter after TBI.
METHODS: The motor evoked potentials (MEPs), open field test, and Morris water maze test were used to assess neurobehavioral outcomes. Brain tissue loss, WM damage, Endoplasmic reticulum stress (ER stress), microglia responses were evaluated after TBI. The functional integrity of WM was measured by diffusion tensor imaging (DTI) and transmission electron microscopy (TEM). Primary microglia and oligodendrocyte cocultures were used for additional mechanistic studies.
RESULTS: JWH133 increased myelin basic protein (MBP) and neurofilament heavy chain (NF200) levels and anatomic preservation of myelinated axons revealed by DTI and TEM. JWH133 also increased the numbers of oligodendrocyte precursor cells and mature oligodendrocytes. Furthermore, JWH133 drove microglial polarization toward the protective M2 phenotype and modulated the redistribution of microglia in the striatum. Further investigation of the underlying mechanism revealed that JWH133 downregulated phosphorylation of the protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK) signaling pathway and its downstream signals eukaryotic translation initiation factor 2 α (eIF2α), activating transcription factor 4 (ATF4) and Growth arrest and DNA damage-inducible protein (GADD34); this downregulation was followed by p-Protein kinase B(p-Akt) upregulation. In primary cocultures of microglia and oligodendrocytes, JWH133 decreased phosphorylated PERK expression in microglia stimulated with tunicamycin and facilitated oligodendrocyte survival. These data reveal that JWH133 ultimately alleviates WMI and improves neurological behavior following TBI. However, these effects were prevented by SR144528, a selective CB2 antagonist.
CONCLUSIONS: This work illustrates the PERK-mediated interaction between microglia and oligodendrocytes. In addition, the results are consistent with recent findings that microglial polarization switching accelerates WMI, highlighting a previously unexplored role for CB2 agonists. Thus, CB2 agonists are potential therapeutic agents for TBI and other neurological conditions involving white matter destruction.

Keywords:  Cannabinoid receptor-2; Endoplasmic reticulum (ER) stress; Microglia/macrophage polarization; Oligodendrocytes; Traumatic brain injury; White matter injury

DOI:  https://doi.org/10.1016/j.expneurol.2021.113899
Brain Behav. 2021 Oct 21. e32365

Anti-PrP monoclonal antibody as a novel treatment for neurogenesis in mouse model of Alzheimer's disease.

Ruolin Li, Ming Ren, Yingxin Yu.

   BACKGROUND: Alzheimer's disease (AD) is the most common degenerative disease characterized by cognitive impairment, memory decline, and language disorder for which there is no effective treatment. Neurogenesis has been indicated in AD and may play an important role in the pathogenesis of AD. Targeting this pathway is a new idea for the treatment of the disease. A recent study reveals that the cellular prion protein (PrP), a receptor for Aβ oligomers, regulates neurogenesis, and its elevated expression is related to cell differentiation. The aim of the present study was to investigate the neuroprotective effects of 6D11 (PrP monoclonal antibody) via neurogenesis promotion in APP/PS1 transgenic mice and Aβ-induced cell model of AD.
METHODS: In the present study, 9-month-old male APP/PS1 mice were injected with 6D11. Then, the Morris water maze was used to examine the spatial learning and memory abilities of the mice in both groups, and immunostained was used to assess the level of Aβ, neurogenesis, and neural stem cells (NSCs) differentiation.
RESULTS: 6D11 attenuated cognitive deficits in APP/PS1 transgenic mice, which was accompanied by a decrease of the deposition of Aβ. In addition, 6D11 treatment promoted differentiation of the existing hippocampal cells to neurons.
CONCLUSIONS: Our findings confirmed that 6D11 has a therapeutic effect in APP/PS1 transgenic AD mouse model and Aβ-induced AD cell model, and the effect exerted via increase of neurogenesis and cell differentiation by transduction of Aβ peptide signal.

Keywords:  6D11; Alzheimer's disease; Aβ; neurogenesis; prion protein

DOI:  https://doi.org/10.1002/brb3.2365
J Cell Sci. 2021 Oct 20. pii: jcs.258785. [Epub ahead of print]

Dynamic remodeling of ribosomes and endoplasmic reticulum in axon terminals of motoneurons.

Chunchu Deng, Mehri Moradi, Sebastian Reinhard, Changhe Ji, Sibylle Jablonka, Luisa Hennlein, Patrick Lüningschrör, Sören Doose, Markus Sauer, Michael Sendtner.

  In neurons, endoplasmic reticulum forms a highly dynamic network that enters axons and presynaptic terminals and plays a central role in Ca2+ homeostasis and synapse maintenance. However, the underlying mechanisms involved in regulation of its dynamic remodeling as well as its function in axon development and presynaptic differentiation remain elusive. Here, we used high resolution microscopy and live cell imaging to investigate rapid movements of endoplasmic reticulum and ribosomes in axons of cultured motoneurons after stimulation with Brain-derived neurotrophic factor. Our results indicate that the endoplasmic reticulum extends into axonal growth cone filopodia where its integrity and dynamic remodeling are regulated mainly by actin and its motor protein myosin VI. Additionally, we found that in axonal growth cones, ribosomes assemble into 80S subunits within seconds and associate with ER in response to extracellular stimuli which describes a novel function of axonal ER in dynamic regulation of local translation.

Keywords:  BDNF stimulation; Dynamics of local translation; ER dynamics in axon terminals

DOI:  https://doi.org/10.1242/jcs.258785
Life (Basel). 2021 Oct 16. pii: 1098. [Epub ahead of print]11(10):

Short-Term Sleep Fragmentation Dysregulates Autophagy in a Brain Region-Specific Manner.

Yan Cheng, Woong-Ki Kim, Laurie L Wellman, Larry D Sanford, Ming-Lei Guo.

  In this study, we investigated autophagy, glial activation status, and corticotropin releasing factor (CRF) signaling in the brains of mice after 5 days of sleep fragmentation (SF). Three different brain regions including the striatum, hippocampus, and frontal cortex were selected for examination based on roles in sleep regulation and sensitivity to sleep disruption. For autophagy, we monitored the levels of various autophagic induction markers including beclin1, LC3II, and p62 as well as the levels of lysosomal associated membrane protein 1 and 2 (LAMP1/2) and the transcription factor EB (TFEB) which are critical for lysosome function and autophagy maturation stage. For the status of microglia and astrocytes, we determined the levels of Iba1 and GFAP in these brain regions. We also measured the levels of CRF and its cognate receptors 1 and 2 (CRFR1/2). Our results showed that 5 days of SF dysregulated autophagy in the striatum and hippocampus but not in the frontal cortex. Additionally, 5 days of SF activated microglia in the striatum but not in the hippocampus or frontal cortex. In the striatum, CRFR2 but not CRFR1 was significantly increased in SF-experienced mice. CRF did not alter its mRNA levels in any of the three brain regions assessed. Our findings revealed that autophagy processes are sensitive to short-term SF in a region-specific manner and suggest that autophagy dysregulation may be a primary initiator for brain changes and functional impairments in the context of sleep disturbances and disorders.

Keywords:  autophagy; corticotropin releasing factor; microglia; neuroinflammation; sleep fragmentation

DOI:  https://doi.org/10.3390/life11101098
Cells. 2021 Oct 16. pii: 2772. [Epub ahead of print]10(10):

Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases.

Claudio Pinto, Elisabetta Ninfole, Antonio Benedetti, Marco Marzioni, Luca Maroni.

  Autophagy is a "housekeeping" lysosomal degradation process involved in numerous physiological and pathological processes in all eukaryotic cells. The dysregulation of hepatic autophagy has been described in several conditions, from obesity to diabetes and cholestatic disease. We review the role of autophagy, focusing on age-related cholestatic diseases, and discuss its therapeutic potential and the molecular targets identified to date. The accumulation of toxic BAs is the main cause of cell damage in cholestasis patients. BAs and their receptor, FXR, have been implicated in the regulation of hepatic autophagy. The mechanisms by which cholestasis induces liver damage include mitochondrial dysfunction, oxidative stress and ER stress, which lead to cell death and ultimately to liver fibrosis as a compensatory mechanism to reduce the damage. The stimulation of autophagy seems to ameliorate the liver damage. Autophagic activity decreases with age in several species, whereas its basic extends lifespan in animals, suggesting that it is one of the convergent mechanisms of several longevity pathways. No strategies aimed at inducing autophagy have yet been tested in cholestasis patients. However, its stimulation can be viewed as a novel therapeutic strategy that may reduce ageing-dependent liver deterioration and also mitigate hepatic steatosis.

Keywords:  FXR; Rubicon; UDCA; ageing; autophagy; cholangiopathies; cholestasis

DOI:  https://doi.org/10.3390/cells10102772
Biology (Basel). 2021 Oct 15. pii: 1047. [Epub ahead of print]10(10):

Tau Post-Translational Modifications: Potentiators of Selective Vulnerability in Sporadic Alzheimer's Disease.

Trae Carroll, Sanjib Guha, Keith Nehrke, Gail V W Johnson.

  Sporadic Alzheimer's Disease (AD) is the most common form of dementia, and its severity is characterized by the progressive formation of tau neurofibrillary tangles along a well-described path through the brain. This spatial progression provides the basis for Braak staging of the pathological progression for AD. Tau protein is a necessary component of AD pathology, and recent studies have found that soluble tau species with selectively, but not extensively, modified epitopes accumulate along the path of disease progression before AD-associated insoluble aggregates form. As such, modified tau may represent a key cellular stressing agent that potentiates selective vulnerability in susceptible neurons during AD progression. Specifically, studies have found that tau phosphorylated at sites such as T181, T231, and S396 may initiate early pathological changes in tau by disrupting proper tau localization, initiating tau oligomerization, and facilitating tau accumulation and extracellular export. Thus, this review elucidates potential mechanisms through which tau post-translational modifications (PTMs) may simultaneously serve as key modulators of the spatial progression observed in AD development and as key instigators of early pathology related to neurodegeneration-relevant cellular dysfunctions.

Keywords:  Alzheimer’s disease; aging; autophagy; neurodegeneration; selective vulnerability; tau; tau PTMs

DOI:  https://doi.org/10.3390/biology10101047
Expert Opin Drug Discov. 2021 Oct 22. 1-4

Can we make drug discovery targeting fundamental mechanisms of aging a reality?

David G Le Couteur, Rozalyn M Anderson, Rafael de Cabo.

DOI: https://doi.org/10.1080/17460441.2022.1993818