bims-proarb 2022-12-25 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2022‒12‒25
eleven papers selected by
Rich Giadone
Harvard University

Aging-accelerated differential production and aggregation of STAT3 protein in neuronal cells and neural stem cells in the male mouse spinal cord.
Amyloid Disassembly: What Can We Learn from Chaperones?
Neurodegeneration Risk Factor, EIF2AK3 (PERK), Influences Tau Protein Aggregation.
Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Vision Loss Patients.
Mechanisms of RNA and Protein Quality Control and Their Roles in Cellular Senescence and Age-Related Diseases.
Eukaryotic translation initiation factor eIF4G2 opens novel paths for protein synthesis in development, apoptosis and cell differentiation.
Mitochondrial Autophagy in Ischemic Aged Livers.
Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte-derived lipid transport.
The global downregulation of protein synthesis observed during hepatogenic maturation is associated with a decrease in TOP mRNA translation.
Regulation of eIF4E guides a unique translational program to control erythroid maturation.
Role of autophagy in lung diseases and ageing.

Biogerontology. 2022 Dec 22.

Aging-accelerated differential production and aggregation of STAT3 protein in neuronal cells and neural stem cells in the male mouse spinal cord.

Tianyi Zhao, Chang Liu, Lihua Liu, Xinmeng Wang, Chao Liu.

  Aging-affected cellular compositions of the spinal cord are diverse and region specific. Age leads to the accumulation of abnormal protein aggregates and dysregulation of proteostasis. Dysregulated proteostasis and protein aggregates result from dysfunction of the ubiquitin-proteasome system (UPS) and autophagy. Understanding the molecular mechanisms of spinal cord aging is essential and important for scientists to discover new therapies for rejuvenation. We found age-related increases in STAT3 and decreases in Tuj1 in aging mouse spinal cords, which was characterized by increased expression of P16. Coaggregation of lysine-48 and lysine-63 ubiquitin with STAT3 was revealed in aging mouse spinal cords. STAT3-ubiquitin aggregates formed via lysine-48 and lysine-63 linkages were increased significantly in the aging spinal cords but not in central canal ependymal cells or neural stem cells in the spinal cord. These results highlight the increase in STAT3 and its region-specific aggregation and ubiquitin-conjugation during spinal cord aging.

Keywords:  Aging; Neural stem cell; STAT3; Spinal cord; Ubiquitin

DOI:  https://doi.org/10.1007/s10522-022-10004-z
Biomedicines. 2022 Dec 17. pii: 3276. [Epub ahead of print]10(12):

Amyloid Disassembly: What Can We Learn from Chaperones?

Zaida L Almeida, Rui M M Brito.

  Protein aggregation and subsequent accumulation of insoluble amyloid fibrils with cross-β structure is an intrinsic characteristic of amyloid diseases, i.e., amyloidoses. Amyloid formation involves a series of on-pathway and off-pathway protein aggregation events, leading to mature insoluble fibrils that eventually accumulate in multiple tissues. In this cascade of events, soluble oligomeric species are formed, which are among the most cytotoxic molecular entities along the amyloid cascade. The direct or indirect action of these amyloid soluble oligomers and amyloid protofibrils and fibrils in several tissues and organs lead to cell death in some cases and organ disfunction in general. There are dozens of different proteins and peptides causing multiple amyloid pathologies, chief among them Alzheimer's, Parkinson's, Huntington's, and several other neurodegenerative diseases. Amyloid fibril disassembly is among the disease-modifying therapeutic strategies being pursued to overcome amyloid pathologies. The clearance of preformed amyloids and consequently the arresting of the progression of organ deterioration may increase patient survival and quality of life. In this review, we compiled from the literature many examples of chemical and biochemical agents able to disaggregate preformed amyloids, which have been classified as molecular chaperones, chemical chaperones, and pharmacological chaperones. We focused on their mode of action, chemical structure, interactions with the fibrillar structures, morphology and toxicity of the disaggregation products, and the potential use of disaggregation agents as a treatment option in amyloidosis.

Keywords:  aberrant aggregates; amyloid disassembly; amyloid fibrils; amyloidosis; chemical chaperones; disaggregases; molecular chaperones; pharmacological chaperones; protein aggregation; protein misfolding

DOI:  https://doi.org/10.3390/biomedicines10123276
J Biol Chem. 2022 Dec 20. pii: S0021-9258(22)01264-9. [Epub ahead of print] 102821

Neurodegeneration Risk Factor, EIF2AK3 (PERK), Influences Tau Protein Aggregation.

Goonho Park, Ke Xu, Leon Chea, Kyle Kim, Lance Safarta, Keon-Hyoung Song, Jian Wu, Soyoung Park, Hyejung Min, Nobuhiko Hiramatsu, Jaeseok Han, Jonathan H Lin.

  Tauopathies are neurodegenerative diseases caused by pathologic misfolded tau protein aggregation in the nervous system. Population studies implicate EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3), better known as PERK (protein kinase R-like endoplasmic reticulum kinase), as a genetic risk factor in several tauopathies. PERK is a key regulator of intracellular proteostatic mechanisms - Unfolded Protein Response (UPR) and Integrated Stress Response (ISR). Previous studies found that tauopathy-associated PERK variants encoded functional hypomorphs with reduced signaling in vitro. But, it remained unclear how altered PERK activity led to tauopathy. Here, we chemically or genetically modulated PERK signaling in cell culture models of tau aggregation and found that PERK pathway activation prevented tau aggregation while inhibition exacerbated tau aggregation. In primary tauopathy patient brain tissues, we found that reduced PERK signaling correlated with increased tau neuropathology. We found that tauopathy-associated PERK variants targeted the ER luminal domain; and two of these variants damaged hydrogen bond formation. Our studies support that PERK activity protects against tau aggregation and pathology. This may explain why people carrying hypomorphic PERK variants have increased risk for developing tauopathies. Finally, our studies identify small molecule augmentation of PERK signaling as an attractive therapeutic strategy to treat tauopathies by preventing tau pathology.

Keywords:  EIF2AK3; ER stress; Integrated Stress Response; Neurodegeneration; PERK; Tau aggregation; Tauopathy; Unfolded Protein Response; eIF2α phosphorylation

DOI:  https://doi.org/10.1016/j.jbc.2022.102821
Am J Pathol. 2022 Dec 16. pii: S0002-9440(22)00397-2. [Epub ahead of print]

Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Vision Loss Patients.

Eun-Jin Lee, Monica Sophia Diaz-Aguilar, Hyejung Min, Jihee Choi, Diego Adrian Valdez Duran, Julia M Grandjean, R Luke Wiseman, Heike Kroeger, Jonathan H Lin.

Activating transcription factor 6 (ATF6), a key regulator of the unfolded protein response (UPR), is required for endoplasmic reticulum (ER) function and protein homeostasis. Variants of ATF6 that abrogate transcriptional activity cause morphologic and molecular defects in cones manifesting clinically as the human vision loss disease achromatopsia (ACHM). ATF6 is expressed in all retinal cells. However, the effect of disease-associated ATF6 variants on other retinal cell types remains unclear. To investigate this question, we analyzed bulk-RNA-seq transcriptomes from retinal-organoids generated from ACHM patients carrying homozygous loss-of-function ATF6 variants. We identified marked dysregulation in mitochondrial respiratory complex gene expression and disrupted mitochondrial morphology in ACHM retinal organoids, indicating that loss of ATF6 leads to previously unappreciated mitochondrial defects in the retina. Next, we compared gene expression from control and ACHM retinal organoids with transcriptome profiles of 7 major retinal cell types generated from recent single-cell transcriptomic maps of non-diseased human retina. Our analysis revealed pronounced down-regulation of cone genes and up-regulation in Müller glia genes, with no significant effects on other retinal cells. Overall, our analysis of ACHM patient retinal organoids identifies new cellular and molecular phenotypes in addition to cone dysfunction: activation of Müller cells, increased ER stress, and disrupted mitochondrial structure and elevated respiratory chain activity gene expression.

DOI: https://doi.org/10.1016/j.ajpath.2022.12.002
Cells. 2022 Dec 15. pii: 4062. [Epub ahead of print]11(24):

Mechanisms of RNA and Protein Quality Control and Their Roles in Cellular Senescence and Age-Related Diseases.

Donghee Kang, Yurim Baek, Jae-Seon Lee.

  Cellular senescence, a hallmark of aging, is defined as irreversible cell cycle arrest in response to various stimuli. It plays both beneficial and detrimental roles in cellular homeostasis and diseases. Quality control (QC) is important for the proper maintenance of cellular homeostasis. The QC machineries regulate the integrity of RNA and protein by repairing or degrading them, and are dysregulated during cellular senescence. QC dysfunction also contributes to multiple age-related diseases, including cancers and neurodegenerative, muscle, and cardiovascular diseases. In this review, we describe the characters of cellular senescence, discuss the major mechanisms of RNA and protein QC in cellular senescence and aging, and comprehensively describe the involvement of these QC machineries in age-related diseases. There are many open questions regarding RNA and protein QC in cellular senescence and aging. We believe that a better understanding of these topics could propel the development of new strategies for addressing age-related diseases.

Keywords:  RNA quality control; age-related diseases; cellular senescence; protein quality control

DOI:  https://doi.org/10.3390/cells11244062
Cell Prolif. 2022 Dec 22. e13367

Eukaryotic translation initiation factor eIF4G2 opens novel paths for protein synthesis in development, apoptosis and cell differentiation.

Yudi Liu, Jiuwei Cui, Andrew R Hoffman, Ji-Fan Hu.

Protein translation is a critical regulatory event involved in nearly all physiological and pathological processes. Eukaryotic translation initiation factors are dedicated to translation initiation, the most highly regulated stage of protein synthesis. Eukaryotic translation initiation factor 4G2 (eIF4G2, also called p97, NAT1 and DAP5), an eIF4G family member that lacks the binding sites for 5' cap binding protein eIF4E, is widely considered to be a key factor for internal ribosome entry sites (IRESs)-mediated cap-independent translation. However, recent findings demonstrate that eIF4G2 also supports many other translation initiation pathways. In this review, we summarize the role of eIF4G2 in a variety of cap-independent and -dependent translation initiation events. Additionally, we also update recent findings regarding the role of eIF4G2 in apoptosis, cell survival, cell differentiation and embryonic development. These studies reveal an emerging new picture of how eIF4G2 utilizes diverse translational mechanisms to regulate gene expression.

DOI: https://doi.org/10.1111/cpr.13367
Cells. 2022 Dec 16. pii: 4083. [Epub ahead of print]11(24):

Mitochondrial Autophagy in Ischemic Aged Livers.

Jae-Sung Kim, William C Chapman, Yiing Lin.

  Mitochondrial autophagy (mitophagy) is a central catabolic event for mitochondrial quality control. Defective or insufficient mitophagy, thus, can result in mitochondrial dysfunction, and ultimately cell death. There is a strong causal relationship between ischemia/reperfusion (I/R) injury and mitochondrial dysfunction following liver resection and transplantation. Compared to young patients, elderly patients poorly tolerate I/R injury. Accumulation of abnormal mitochondria after I/R is more prominent in aged livers than in young counterparts. This review highlights how altered autophagy is mechanistically involved in age-dependent hypersensitivity to reperfusion injury.

Keywords:  autophagy; ischemia/reperfusion; liver; mitochondria; mitochondrial dynamics

DOI:  https://doi.org/10.3390/cells11244083
J Neurochem. 2022 Dec 22.

Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte-derived lipid transport.

Kingston King-Shi Mok, Sunny Hoi-Sang Yeung, Gerald Wai-Yeung Cheng, Iris Wai-Ting Ma, Ralph Hon-Sun Lee, Karl Herrup, Kai-Hei Tse.

  Carriers of the APOE4 (Apolipoprotein E ε4) variant of the APOE gene are subject to several age-related health risks, including Alzheimer's disease (AD). The deficient lipid and cholesterol transport capabilities of the APOE4 protein are one reason for the altered risk profile. In particular, APOE4 carriers are at elevated risk for sporadic Alzheimer's disease (AD). While deposits o misfolded proteins are present in the AD brain, white matter (WM) myelin is also disturbed. As myelin is a lipid- and cholesterol-rich structure, the connection to APOE makes considerable biological sense. To explore the APOE-WM connection, we have analyzed the impact of human APOE4 on oligodendrocytes (OLs) of the mouse both in vivo and in vitro. We find that APOE proteins is enriched in astrocytes but sparse in OL. In human APOE4 (hAPOE4) knockin mice, myelin lipid content is increased but the density of major myelin proteins (MBP, MAG and PLP) is largely unchanged. We also find an unexpected but significant reduction of cell density of the OL lineage (Olig2+ ) and an abnormal accumulation of OL precursors (Nkx 2.2+ ), suggesting a disruption of OL differentiation. Gene ontology analysis of an existing RNA-seq dataset confirms a robust transcriptional response to the altered chemistry of the hAPOE4 mouse brain. In culture, the uptake of astrocyte-derived APOE during Lovastatin-mediated depletion of cholesterol synthesis is sufficient to sustain OL differentiation. While endogenous hAPOE protein isoforms have no effects on OL development, exogenous hAPOE4 abolishes the ability of very low-density lipoprotein to restore myelination in Apoe-deficient, cholesterol-depleted OL. Our data suggest that APOE4 impairs myelination in the aging brain by interrupting the delivery of astrocyte-derived lipids to the oligodendrocytes. We propose that high myelin turnover and OL exhaustion found in APOE4 carriers is a likely explanation for the APOE-dependent myelin phenotypes of the AD brain.

Keywords:  APOE4; Alzheimer's disease; Astrocyte; Lipid transport; Myelin; Oligodendrocyte

DOI:  https://doi.org/10.1111/jnc.15748
Stem Cell Reports. 2022 Dec 02. pii: S2213-6711(22)00553-7. [Epub ahead of print]

The global downregulation of protein synthesis observed during hepatogenic maturation is associated with a decrease in TOP mRNA translation.

Marino Caruso, Sébastien Meurant, Damien Detraux, Amandine Mathieu, Manon Gilson, Marc Dieu, Antoine Fattaccioli, Catherine Demazy, Mustapha Najimi, Etienne Sokal, Thierry Arnould, Catherine Verfaillie, Denis L J Lafontaine, Patricia Renard.

  Translational regulation is of paramount importance for proteome remodeling during stem cell differentiation at both the global and the transcript-specific levels. In this study, we characterized translational remodeling during hepatogenic differentiation of induced pluripotent stem cells (iPSCs) by polysome profiling. We demonstrate that protein synthesis increases during exit from pluripotency and is then globally repressed during later steps of hepatogenic maturation. This global downregulation of translation is accompanied by a decrease in the abundance of protein components of the translation machinery, which involves a global reduction in translational efficiency of terminal oligopyrimidine tract (TOP) mRNA encoding translation-related factors. Despite global translational repression during hepatogenic differentiation, key hepatogenic genes remain efficiently translated, and the translation of several transcripts involved in hepatospecific functions and metabolic maturation is even induced. We conclude that, during hepatogenic differentiation, a global decrease in protein synthesis is accompanied by a specific translational rewiring of hepatospecific transcripts.

Keywords:  LARP1; TOP mRNA; hepatocyte differentiation; iPSC; polysome profiling; stem cells; translational regulation

DOI:  https://doi.org/10.1016/j.stemcr.2022.11.020
Sci Adv. 2022 Dec 23. 8(51): eadd3942

Regulation of eIF4E guides a unique translational program to control erythroid maturation.

Craig M Forester, Juan A Oses-Prieto, Nancy J Phillips, Sohit Miglani, Xiaming Pang, Gun Woo Byeon, Rachel DeMarco, Al Burlingame, Maria Barna, Davide Ruggero.

Translation control is essential in balancing hematopoietic precursors and differentiation; however, the mechanisms underlying this program are poorly understood. We found that the activity of the major cap-binding protein eIF4E is unexpectedly regulated in a dynamic manner throughout erythropoiesis that is uncoupled from global protein synthesis rates. Moreover, eIF4E activity directs erythroid maturation, and increased eIF4E expression maintains cells in an early erythroid state associated with a translation program driving the expression of PTPN6 and Igf2bp1. A cytosine-enriched motif in the 5' untranslated region is important for eIF4E-mediated translation specificity. Therefore, selective translation of key target genes necessary for the maintenance of early erythroid states by eIF4E highlights a unique mechanism used by hematopoietic precursors to rapidly elicit erythropoietic maturation upon need.

DOI: https://doi.org/10.1126/sciadv.add3942
Eur Respir Rev. 2022 Dec 31. pii: 220134. [Epub ahead of print]31(166):

Role of autophagy in lung diseases and ageing.

Yan Zhang, Jin Zhang, Zhiling Fu.

The lungs face ongoing chemical, mechanical, biological, immunological and xenobiotic stresses over a lifetime. Advancing age progressively impairs lung function. Autophagy is a "housekeeping" survival strategy involved in numerous physiological and pathological processes in all eukaryotic cells. Autophagic activity decreases with age in several species, whereas its basic activity extends throughout the lifespan of most animals. Dysregulation of autophagy has been proven to be closely related to the pathogenesis of several ageing-related pulmonary diseases. This review summarises the role of autophagy in the pathogenesis of pulmonary diseases associated with or occurring in the context of ageing, including acute lung injury, chronic obstructive pulmonary disease, asthma and pulmonary fibrosis, and describes its potential as a therapeutic target.

DOI: https://doi.org/10.1183/16000617.0134-2022