bims-proarb 2022-04-03 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2022‒04‒03
ten papers selected by
Rich Giadone
Harvard University

Contribution of proteases to the hallmarks of aging and to age-related neurodegeneration.
Biosensors for Studying Neuronal Proteostasis.
Protein quality control at the Golgi.
Tau propagation is dependent on the genetic background of mouse strains.
eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of stem cell pluripotency.
Dedicated chaperones coordinate co-translational regulation of ribosomal protein production with ribosome assembly to preserve proteostasis.
Phosphorylated resveratrol as a protein aggregation suppressor in vitro and in vivo.
Blood-brain barrier dysfunction and reduced cerebrospinal fluid levels of soluble amyloid precursor protein-β in patients with subcortical small-vessel disease.
O-GlcNAcase Inhibitor ASN90 is a Multimodal Drug Candidate for Tau and α-Synuclein Proteinopathies.
Age-dependent formation of TMEM106B amyloid filaments in human brains.

Aging Cell. 2022 Mar 29. e13603

Contribution of proteases to the hallmarks of aging and to age-related neurodegeneration.

Mamta Rai, Michelle Curley, Zane Coleman, Fabio Demontis.

  Protein quality control ensures the degradation of damaged and misfolded proteins. Derangement of proteostasis is a primary cause of aging and age-associated diseases. The ubiquitin-proteasome and autophagy-lysosome play key roles in proteostasis but, in addition to these systems, the human genome encodes for ~600 proteases, also known as peptidases. Here, we examine the role of proteases in aging and age-related neurodegeneration. Proteases are present across cell compartments, including the extracellular space, and their substrates encompass cellular constituents, proteins with signaling functions, and misfolded proteins. Proteolytic processing by proteases can lead to changes in the activity and localization of substrates or to their degradation. Proteases cooperate with the autophagy-lysosome and ubiquitin-proteasome systems but also have independent proteolytic roles that impact all hallmarks of cellular aging. Specifically, proteases regulate mitochondrial function, DNA damage repair, cellular senescence, nutrient sensing, stem cell properties and regeneration, protein quality control and stress responses, and intercellular signaling. The capacity of proteases to regulate cellular functions translates into important roles in preserving tissue homeostasis during aging. Consequently, proteases influence the onset and progression of age-related pathologies and are important determinants of health span. Specifically, we examine how certain proteases promote the progression of Alzheimer's, Huntington's, and/or Parkinson's disease whereas other proteases protect from neurodegeneration. Mechanistically, cleavage by proteases can lead to the degradation of a pathogenic protein and hence impede disease pathogenesis. Alternatively, proteases can generate substrate byproducts with increased toxicity, which promote disease progression. Altogether, these studies indicate the importance of proteases in aging and age-related neurodegeneration.

Keywords:  aging; extracellular proteostasis; neurodegeneration; peptidase; protease; proteolysis

DOI:  https://doi.org/10.1111/acel.13603
Front Mol Neurosci. 2022 ;15 829365

Biosensors for Studying Neuronal Proteostasis.

Irina Dudanova.

  Cellular health depends on the integrity and functionality of the proteome. Each cell is equipped with a protein quality control machinery that maintains protein homeostasis (proteostasis) by helping proteins adopt and keep their native structure, and ensuring the degradation of damaged proteins. Postmitotic cells such as neurons are especially vulnerable to disturbances of proteostasis. Defects of protein quality control occur in aging and have been linked to several disorders, including neurodegenerative diseases. However, the exact nature and time course of such disturbances in the context of brain diseases remain poorly understood. Sensors that allow visualization and quantitative analysis of proteostasis capacity in neurons are essential for gaining a better understanding of disease mechanisms and for testing potential therapies. Here, I provide an overview of available biosensors for assessing the functionality of the neuronal proteostasis network, point out the advantages and limitations of different sensors, and outline their potential for biological discoveries and translational applications.

Keywords:  biosensor; neuron; protein folding; protein misfolding diseases; protein quality control; proteostasis

DOI:  https://doi.org/10.3389/fnmol.2022.829365
Curr Opin Cell Biol. 2022 Mar 29. pii: S0955-0674(22)00020-5. [Epub ahead of print]75 102074

Protein quality control at the Golgi.

Sinead Schwabl, David Teis.

The majority of the proteome in eukaryotic cells is targeted to organelles. To maintain protein homeostasis (proteostasis), distinct protein quality control (PQC) machineries operate on organelles, where they detect misfolded proteins, orphaned and mis-localized proteins and selectively target these proteins into different ubiquitin-dependent or -independent degradation pathways. Thereby, PQC prevents proteotoxic effects that would disrupt organelle integrity and cause cellular damage that leads to diseases. Here, we will discuss emerging mechanisms for PQC machineries at the Golgi apparatus, the central station for the sorting and the modification of proteins that traffic to the endo-lysosomal system, or along the secretory pathway to the PM and to the extracellular space. We will focus on Golgi PQC pathways that (1) retrieve misfolded and orphaned proteins from the Golgi back to the endoplasmic reticulum, (2) extract these proteins from Golgi membranes for proteasomal degradation, (3) or selectively target these proteins to lysosomes for degradation.

DOI: https://doi.org/10.1016/j.ceb.2022.02.008
Brain Commun. 2022 ;4(2): fcac048

Tau propagation is dependent on the genetic background of mouse strains.

Simon Dujardin, Analiese Fernandes, Riley Bannon, Caitlin Commins, Mark De Los Santos, Tarun V Kamath, Mansuo Hayashi, Bradley T Hyman.

  Progressive cognitive decline in Alzheimer's disease correlates closely with the spread of tau protein aggregation across neural networks of the cortical mantle. We tested the hypothesis that heritable factors may influence the rate of propagation of tau pathology across brain regions in a model system, taking advantage of well-defined genetically diverse background strains in mice. We virally expressed human tau locally in the hippocampus and the entorhinal cortex neurons and monitored the cell-to-cell tau protein spread by immunolabelling. Interestingly, some strains showed more tau spreading than others while tau misfolding accumulated at the same rate in all tested mouse strains. Genetic factors may contribute to tau pathology progression across brain networks, which could help refine mechanisms underlying tau cell-to-cell transfer and accumulation, and potentially provide targets for understanding patient-to-patient variability in the rate of disease progression in Alzheimer's disease.

Keywords:  Alzheimer’s disease; cell-to-cell transfer; genetic background; tau spreading; tauopathies

DOI:  https://doi.org/10.1093/braincomms/fcac048
Sci Adv. 2022 Apr;8(13): eabm0478

eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of stem cell pluripotency.

Dan Li, Jihong Yang, Xin Huang, Hongwei Zhou, Jianlong Wang.

Translational control has emerged as a fundamental regulatory layer of proteome complexity that governs cellular identity and functions. As initiation is the rate-limiting step of translation, we carried out an RNA interference screen for key translation initiation factors required to maintain embryonic stem cell (ESC) identity. We identified eukaryotic translation initiation factor 4A2 (eIF4A2) and defined its mechanistic action through ribosomal protein S26-independent and -dependent ribosomes in translation initiation activation of messenger RNAs (mRNAs) encoding pluripotency factors and the histone variant H3.3 with demonstrated roles in maintaining stem cell pluripotency. eIF4A2 also mediates translation initiation activation of Ddx6, which acts together with eIF4A2 to restrict the totipotent two-cell transcription program in ESCs through Zscan4 mRNA degradation and translation repression. Accordingly, knockdown of eIF4A2 disrupts ESC proteome, causing the loss of ESC identity. Collectively, we establish a translational paradigm of the protein synthesis of pluripotency transcription factors and epigenetic regulators imposed on their established roles in controlling pluripotency.

DOI: https://doi.org/10.1126/sciadv.abm0478
Elife. 2022 Mar 31. pii: e74255. [Epub ahead of print]11

Dedicated chaperones coordinate co-translational regulation of ribosomal protein production with ribosome assembly to preserve proteostasis.

Benjamin Pillet, Alfonso Méndez-Godoy, Guillaume Murat, Sébastien Favre, Michael Stumpe, Laurent Falquet, Dieter Kressler.

  The biogenesis of eukaryotic ribosomes involves the ordered assembly of around 80 ribosomal proteins. Supplying equimolar amounts of assembly-competent ribosomal proteins is complicated by their aggregation propensity and the spatial separation of their location of synthesis and pre-ribosome incorporation. Recent evidence has highlighted that dedicated chaperones protect individual, unassembled ribosomal proteins on their path to the pre-ribosomal assembly site. Here, we show that the co-translational recognition of Rpl3 and Rpl4 by their respective dedicated chaperone, Rrb1 or Acl4, reduces the degradation of the encoding RPL3 and RPL4 mRNAs in the yeast Saccharomyces cerevisiae. In both cases, negative regulation of mRNA levels occurs when the availability of the dedicated chaperone is limited and the nascent ribosomal protein is instead accessible to a regulatory machinery consisting of the nascent-polypeptide-associated complex and the Caf130-associated Ccr4-Not complex. Notably, deregulated expression of Rpl3 and Rpl4 leads to their massive aggregation and a perturbation of overall proteostasis in cells lacking the E3 ubiquitin ligase Tom1. Taken together, we have uncovered an unprecedented regulatory mechanism that adjusts the de novo synthesis of Rpl3 and Rpl4 to their actual consumption during ribosome assembly and, thereby, protects cells from the potentially detrimental effects of their surplus production.

Keywords:  Ccr4-Not complex; S. cerevisiae; cell biology; chromosomes; gene expression; mRNA degradation; protein aggregation; protein homeostasis; ribosome biogenesis; yeast genetics

DOI:  https://doi.org/10.7554/eLife.74255
RSC Chem Biol. 2022 Feb 09. 3(2): 250-260

Phosphorylated resveratrol as a protein aggregation suppressor in vitro and in vivo.

Johannes Mehringer, Juan Antonio Navarro, Didier Touraud, Stephan Schneuwly, Werner Kunz.

The stability of proteins in solution poses a great challenge for both technical applications and molecular biology, including neurodegenerative diseases. In this work, a phosphorylated resveratrol material was examined for its anti-aggregation properties in vitro and in vivo. Here, an anti-fibrillation effect could be measured for amyloid beta and human insulin in vitro and general anti-aggregation properties for crude chicken egg white in solution. Using a drosophila fly model for the overexpression of amyloid beta protein, changes in physiological protein aggregation and improved locomotor abilities could be observed in the presence of dietary phosphorylated resveratrol.

DOI: https://doi.org/10.1039/d1cb00220a
Alzheimers Dement (Amst). 2022 ;14(1): e12296

Blood-brain barrier dysfunction and reduced cerebrospinal fluid levels of soluble amyloid precursor protein-β in patients with subcortical small-vessel disease.

Petronella Kettunen, Maria Bjerke, Carl Eckerström, Michael Jonsson, Henrik Zetterberg, Kaj Blennow, Johan Svensson, Anders Wallin.

  Introduction: Subcortical small-vessel disease (SSVD) is the most common vascular cognitive disorder. However, because no disease-specific cerebrospinal fluid (CSF) biomarkers are available for SSVD, our aim was to identify such markers.Methods: We included 170 healthy controls and patients from the Gothenburg Mild Cognitive Impairment (MCI) study clinically diagnosed with SSVD dementia, Alzheimer's disease (AD), or mixed AD/SSVD. We quantified CSF levels of amyloid-β (Aβ)x-38, Aβx-40, Aβx-42, as well as soluble amyloid precursor protein (sAPP)-α and sAPP-β.
Results: sAPP-β was lower in SSVD patients than in AD patients and controls. Receiver-operating characteristic (ROC) analyses showed that sAPP-β moderately separated SSVD from AD and controls. Moreover, the CSF/serum albumin ratio was elevated exclusively in SSVD and could moderately separate SSVD from the other groups in ROC analyses.
Discussion: SSVD has a biomarker profile that differs from that of AD and controls, and to some extent also from mixed AD/SSVD, suggesting that signs of blood-brain barrier (BBB) dysfunction and sAPP-β could be additional tools to diagnose SSVD.
Highlights: Patients with subcortical small-vessel disease (SSVD) exhibited reduced levels of sAPP-β and disturbances of the blood-brain barrier (BBB).This biochemical pattern is different from that of Alzheimer's disease (AD) and to some degree from that of mixed AD/SSVD.Our findings are speaking in favor of the concept that SSVD is a distinct vascular cognitive disorder (VCD) form.

Keywords:  Alzheimer's disease; amyloid beta; blood‐brain barrier; cerebrospinal fluid; subcortical small‐vessel disease

DOI:  https://doi.org/10.1002/dad2.12296
ACS Chem Neurosci. 2022 Mar 31.

O-GlcNAcase Inhibitor ASN90 is a Multimodal Drug Candidate for Tau and α-Synuclein Proteinopathies.

Bruno Permanne, Astrid Sand, Solenne Ousson, Maud Nény, Jennifer Hantson, Ryan Schubert, Christoph Wiessner, Anna Quattropani, Dirk Beher.

  Neurodegenerative proteinopathies are characterized by the intracellular formation of insoluble and toxic protein aggregates in the brain that are closely linked to disease progression. In Alzheimer's disease and in rare tauopathies, aggregation of the microtubule-associated tau protein leads to the formation of neurofibrillary tangles (NFT). In Parkinson's disease (PD) and other α-synucleinopathies, intracellular Lewy bodies containing aggregates of α-synuclein constitute the pathological hallmark. Inhibition of the glycoside hydrolase O-GlcNAcase (OGA) prevents the removal of O-linked N-acetyl-d-glucosamine (O-GlcNAc) moieties from intracellular proteins and has emerged as an attractive therapeutic approach to prevent the formation of tau pathology. Like tau, α-synuclein is known to be modified with O-GlcNAc moieties and in vitro these have been shown to prevent its aggregation and toxicity. Here, we report the preclinical discovery and development of a novel small molecule OGA inhibitor, ASN90. Consistent with the substantial exposure of the drug and demonstrating target engagement in the brain, the clinical OGA inhibitor ASN90 promoted the O-GlcNAcylation of tau and α-synuclein in brains of transgenic mice after daily oral dosing. Across human tauopathy mouse models, oral administration of ASN90 prevented the development of tau pathology (NFT formation), functional deficits in motor behavior and breathing, and increased survival. In addition, ASN90 slowed the progression of motor impairment and reduced astrogliosis in a frequently utilized α-synuclein-dependent preclinical rodent model of PD. These findings provide a strong rationale for the development of OGA inhibitors as disease-modifying agents in both tauopathies and α-synucleinopathies. Since tau and α-synuclein pathologies frequently co-exist in neurodegenerative diseases, OGA inhibitors represent unique, multimodal drug candidates for further clinical development.

Keywords:  Alzheimer’s disease; O-GlcNAcase inhibitor; Parkinson’s disease; drug development; microtubule-associated protein tau; proteinopathies; α-synuclein

DOI:  https://doi.org/10.1021/acschemneuro.2c00057
Nature. 2022 Mar 28.

Age-dependent formation of TMEM106B amyloid filaments in human brains.

Manuel Schweighauser, Diana Arseni, Mehtap Bacioglu, Melissa Huang, Sofia Lövestam, Yang Shi, Yang Yang, Wenjuan Zhang, Abhay Kotecha, Holly J Garringer, Ruben Vidal, Grace I Hallinan, Kathy L Newell, Airi Tarutani, Shigeo Murayama, Masayuki Miyazaki, Yuko Saito, Mari Yoshida, Kazuko Hasegawa, Tammaryn Lashley, Tamas Revesz, Gabor G Kovacs, John van Swieten, Masaki Takao, Masato Hasegawa, Bernardino Ghetti, Maria Grazia Spillantini, Benjamin Ryskeldi-Falcon, Alexey G Murzin, Michel Goedert, Sjors H W Scheres.

Many age-dependent neurodegenerative diseases, like Alzheimer's and Parkinson's, are characterised by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-β (Aβ), α-synuclein and TDP-43 are the most common1,2. Here, we used electron cryo-microscopy (cryo-EM) structure determination to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in human brains. We determined the cryo-EM structures of TMEM106B filaments from a number of brain regions of 22 individuals with abundant amyloid deposits, including sporadic and inherited tauopathies, Aβ-amyloidoses, synucleinopathies and TDP-43 proteinopathies, as well as from the frontal cortex of 3 neurologically normal individuals with no or only few amyloid deposits. We observed three TMEM106B folds, with no clear relationships between folds and diseases. TMEM106B filaments correlated with the presence of a 29 kDa sarkosyl-insoluble fragment and globular cytoplasmic inclusions, as detected by an antibody specific for the C-terminal region of TMEM106B. The identification of TMEM106B filaments in the brains of older, but not younger, neurologically normal individuals indicates that they form in an age-dependent manner.

DOI: https://doi.org/10.1038/s41586-022-04650-z