bims-proned 2023-07-09 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2023–07–09
nine papers selected by
Verena Kohler, University of Graz

Endocytic pathways of pathogenic protein aggregates in neurodegenerative diseases.
TXNIP: A key protein in the cellular stress response pathway and a potential therapeutic target.
CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis.
Disrupting pathologic phase transitions in neurodegeneration.
Leaderless secretory proteins of the neurodegenerative diseases via TNTs: a structure-function perspective.
Natural plant materials as a source of neuroprotective peptides.
Hitting the mark: Localization of mRNA and biomolecular condensates in health and disease.
Intercellular transmission of pathogenic proteins in ALS: Exploring the pathogenic wave.
Preface: Special issue "Brain Proteostasis in Health and Disease".

Traffic. 2023 Jul 01.

Endocytic pathways of pathogenic protein aggregates in neurodegenerative diseases.

Pravin Hivare, Kratika Mujmer, Gitanjali Swarup, Sharad Gupta, Dhiraj Bhatia.

  Endocytosis is the fundamental uptake process through which cells internalize extracellular materials and species. Neurodegenerative diseases (NDs) are characterized by a progressive accumulation of intrinsically disordered protein species, leading to neuronal death. Misfolding in many proteins leads to various NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and other disorders. Despite the significance of disordered protein species in neurodegeneration, their spread between cells and the cellular uptake of extracellular species is not entirely understood. This review discusses the major internalization mechanisms of the different conformer species of these proteins and their endocytic mechanisms. We briefly introduce the broad types of endocytic mechanisms found in cells and then summarize what is known about the endocytosis of monomeric, oligomeric and aggregated conformations of tau, Aβ, α-Syn, Huntingtin, Prions, SOD1, TDP-43 and other proteins associated with neurodegeneration. We also highlight the key players involved in internalizing these disordered proteins and the several techniques and approaches to identify their endocytic mechanisms. Finally, we discuss the obstacles involved in studying the endocytosis of these protein species and the need to develop better techniques to elucidate the uptake mechanisms of a particular disordered protein species.

Keywords:  Huntingtin; amyloid-beta (Aβ); endocytosis; intrinsically disordered proteins; neurodegenerative diseases; tau; α-Synuclein (α-Syn)

DOI:  https://doi.org/10.1111/tra.12906
Exp Mol Med. 2023 Jul 03.

TXNIP: A key protein in the cellular stress response pathway and a potential therapeutic target.

Eui-Hwan Choi, Sun-Ji Park.

Thioredoxin-interacting protein (TXNIP), which is also known as thioredoxin-binding protein 2 (TBP2), directly interacts with the major antioxidant protein thioredoxin (TRX) and inhibits its antioxidant function and expression. However, recent studies have demonstrated that TXNIP is a multifunctional protein with functions beyond increasing intracellular oxidative stress. TXNIP activates endoplasmic reticulum (ER) stress-mediated nucleotide-binding oligomerization domain (NOD)-like receptor protein-3 (NLRP3) inflammasome complex formation, triggers mitochondrial stress-induced apoptosis, and stimulates inflammatory cell death (pyroptosis). These newly discovered functions of TXNIP highlight its role in disease development, especially in response to several cellular stress factors. In this review, we provide an overview of the multiple functions of TXNIP in pathological conditions and summarize its involvement in various diseases, such as diabetes, chronic kidney disease, and neurodegenerative diseases. We also discuss the potential of TXNIP as a therapeutic target and TXNIP inhibitors as novel therapeutic drugs for treating these diseases.

DOI: https://doi.org/10.1038/s12276-023-01019-8
bioRxiv. 2023 Jun 26. pii: 2023.06.16.545386. [Epub ahead of print]

CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis.

Avi J Samelson, Nabeela Ariqat, Justin McKetney, Gita Rohanitazangi, Celeste Parra Bravo, Darrin Goodness, Ruilin Tian, Parker Grosjean, Romany Abskharon, David Eisenberg, Nicholas M Kanaan, Li Gan, Carlo Condello, Danielle L Swaney, Martin Kampmann.

A hallmark of age-associated neurodegenerative diseases is the aggregation of proteins. Aggregation of the protein tau defines tauopathies, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to the accumulation of tau aggregates, and subsequent dysfunction and death. The mechanisms underlying cell type-selective vulnerability are unknown. To systematically uncover the cellular factors controlling the accumulation of tau aggregates in human neurons, we conducted a genome-wide CRISPRi-based modifier screen in iPSC-derived neurons. The screen uncovered expected pathways, including autophagy, but also unexpected pathways including UFMylation and GPI anchor synthesis, that control tau oligomer levels. We identify the E3 ubiquitin ligase CUL5 as a tau interactor and potent modifier of tau levels. In addition, disruption of mitochondrial function increases tau oligomer levels and promotes proteasomal misprocessing of tau. These results reveal new principles of tau proteostasis in human neurons and pinpoint potential therapeutic targets for tauopathies.

DOI: https://doi.org/10.1101/2023.06.16.545386
J Clin Invest. 2023 07 03. pii: e168549. [Epub ahead of print]133(13):

Disrupting pathologic phase transitions in neurodegeneration.

Bryan T Hurtle, Longxin Xie, Christopher J Donnelly.

Solid-like protein deposits found in aged and diseased human brains have revealed a relationship between insoluble protein accumulations and the resulting deficits in neurologic function. Clinically diverse neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis, exhibit unique and disease-specific biochemical protein signatures and abnormal protein depositions that often correlate with disease pathogenesis. Recent evidence indicates that many pathologic proteins assemble into liquid-like protein phases through the highly coordinated process of liquid-liquid phase separation. Over the last decade, biomolecular phase transitions have emerged as a fundamental mechanism of cellular organization. Liquid-like condensates organize functionally related biomolecules within the cell, and many neuropathology-associated proteins reside within these dynamic structures. Thus, examining biomolecular phase transitions enhances our understanding of the molecular mechanisms mediating toxicity across diverse neurodegenerative diseases. This Review explores the known mechanisms contributing to aberrant protein phase transitions in neurodegenerative diseases, focusing on tau and TDP-43 proteinopathies and outlining potential therapeutic strategies to regulate these pathologic events.

DOI: https://doi.org/10.1172/JCI168549
Front Mol Neurosci. 2023 ;16 983108

Leaderless secretory proteins of the neurodegenerative diseases via TNTs: a structure-function perspective.

Sreedevi Padmanabhan, Ravi Manjithaya.

  Neurodegenerative disease-causing proteins such as alpha-synuclein, tau, and huntingtin are known to traverse across cells via exosomes, extracellular vesicles and tunneling nanotubes (TNTs). There seems to be good synergy between exosomes and TNTs in intercellular communication. Interestingly, many of the known major neurodegenerative proteins/proteolytic products are leaderless and are also reported to be secreted out of the cell via unconventional protein secretion. Such classes contain intrinsically disordered proteins and regions (IDRs) within them. The dynamic behavior of these proteins is due to their heterogenic conformations that is exhibited owing to various factors that occur inside the cells. The amino acid sequence along with the chemical modifications has implications on the functional roles of IDRs inside the cells. Proteins that form aggregates resulting in neurodegeneration become resistant to degradation by the processes of autophagy and proteasome system thus leading to Tunneling nanotubes, TNT formation. The proteins that traverse across TNTs may or may not be dependent on the autophagy machinery. It is not yet clear whether the conformation of the protein plays a crucial role in its transport from one cell to another without getting degraded. Although there is some experimental data, there are many grey areas which need to be revisited. This review provides a different perspective on the structural and functional aspects of these leaderless proteins that get secreted outside the cell. In this review, attention has been focused on the characteristic features that lead to aggregation of leaderless secretory proteins (from structural-functional aspect) with special emphasis on TNTs.

Keywords:  autophagy; intrinsic disordered regions; leaderless proteins; neurodegenerative disease; tunneling nanotubes; unconventional protein secretion

DOI:  https://doi.org/10.3389/fnmol.2023.983108
Curr Med Chem. 2023 Jul 03.

Natural plant materials as a source of neuroprotective peptides.

Agnieszka Skibska, Renata Perlikowska.

  In many circumstances, some crucial elements of the neuronal defense system fail, slowly leading to neurodegenerative diseases. Activating this natural process by administering exogenous agents to counteract unfavourable changes seems promising. Therefore, looking for neuroprotective therapeutics, we have to focus on compounds that inhibit the primary mechanisms leading to neuronal injuries, e.g., apoptosis, excitotoxicity, oxidative stress, and inflammation. Among many compounds considered neuroprotective agents, protein hydrolysates and peptides derived from natural materials or their synthetic analogues are good candidates. They have several advantages, such as high selectivity and biological activity, a broad range of targets, and high safety profile. This review aims to provide biological activities, the mechanism of action and the functional properties of plant-derived protein hydrolysates and peptides. We focused on their significant role in human health by affecting the nervous system and having neuroprotective and brain-boosting properties, leading to memory and cognitive improving activities. We hope our observation may guide the evaluation of novel peptides with potential neuroprotective effects. Research into neuroprotective peptides may find application in different sectors as ingredients in functional foods or pharmaceuticals to improve human health and prevent diseases.

Keywords:  antioxidants; bioactive peptides; food intake; hydrolysate; neurodegenerative diseases; neuroprotection; oxidative stress; plant-derived materials

DOI:  https://doi.org/10.2174/0929867331666230703145043
Wiley Interdiscip Rev RNA. 2023 Jul 02. e1807

Hitting the mark: Localization of mRNA and biomolecular condensates in health and disease.

Jessica P Otis, Kimberly L Mowry.

  Subcellular mRNA localization is critical to a multitude of biological processes such as development of cellular polarity, embryogenesis, tissue differentiation, protein complex formation, cell migration, and rapid responses to environmental stimuli and synaptic depolarization. Our understanding of the mechanisms of mRNA localization must now be revised to include formation and trafficking of biomolecular condensates, as several biomolecular condensates that transport and localize mRNA have recently been discovered. Disruptions in mRNA localization can have catastrophic effects on developmental processes and biomolecular condensate biology and have been shown to contribute to diverse diseases. A fundamental understanding of mRNA localization is essential to understanding how aberrations in this biology contribute the etiology of numerous cancers though support of cancer cell migration and biomolecular condensate dysregulation, as well as many neurodegenerative diseases, through misregulation of mRNA localization and biomolecular condensate biology. This article is categorized under: RNA Export and Localization > RNA Localization RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development.

Keywords:  RNA localization; RNPs; biomolecular condensates

DOI:  https://doi.org/10.1002/wrna.1807
Neurobiol Dis. 2023 Jun 30. pii: S0969-9961(23)00233-4. [Epub ahead of print]184 106218

Intercellular transmission of pathogenic proteins in ALS: Exploring the pathogenic wave.

F J Arnold, A D Nguyen, R S Bedlack, C L Bennett, A R La Spada.

  In patients with amyotrophic lateral sclerosis (ALS), disease symptoms and pathology typically spread in a predictable spatiotemporal pattern beginning at a focal site of onset and progressing along defined neuroanatomical tracts. Like other neurodegenerative diseases, ALS is characterized by the presence of protein aggregates in postmortem patient tissue. Cytoplasmic, ubiquitin-positive aggregates of TDP-43 are observed in approximately 97% of sporadic and familial ALS patients, while SOD1 inclusions are likely specific to cases of SOD1-ALS. Additionally, the most common subtype of familial ALS, caused by a hexanucleotide repeat expansion in the first intron of the C9orf72 gene (C9-ALS), is further characterized by the presence of aggregated dipeptide repeat proteins (DPRs). As we will describe, cell-to-cell propagation of these pathological proteins tightly correlates with the contiguous spread of disease. While TDP-43 and SOD1 are capable of seeding protein misfolding and aggregation in a prion-like manner, C9orf72 DPRs appear to induce (and transmit) a 'disease state' more generally. Multiple mechanisms of intercellular transport have been described for all of these proteins, including anterograde and retrograde axonal transport, extracellular vesicle secretion, and macropinocytosis. In addition to neuron-to-neuron transmission, transmission of pathological proteins occurs between neurons and glia. Given that the spread of ALS disease pathology corresponds with the spread of symptoms in patients, the various mechanisms by which ALS-associated protein aggregates propagate through the central nervous system should be closely examined.

Keywords:  ALS; Cell-to-cell propagation; Endocytosis; Extracellular-vesicles; Oligomerization

DOI:  https://doi.org/10.1016/j.nbd.2023.106218
J Neurochem. 2023 Jul;166(1): 3-6

Preface: Special issue "Brain Proteostasis in Health and Disease".

Mychael V Lourenco.

This preface introduces the Journal of Neurochemistry Special Issue on Brain Proteostasis. Adequate control of protein homeostasis, or proteostasis, has been at the center stage of brain physiology, and its deregulation may contribute to brain diseases, including several neuropsychiatric and neurodegenerative conditions. Therefore, delineating the processes underlying protein synthesis, folding, stability, function, and degradation in brain cells is key to promoting brain function and identifying effective therapeutic options for neurological disorders. This special issue comprises four review articles and four original articles covering the roles of protein homeostasis in several mechanisms that are of relevance to sleep, depression, stroke, dementia, and COVID-19. Thus, these articles highlight different aspects of proteostasis regulation in the brain and present important evidence on this growing and exciting field.

DOI: https://doi.org/10.1111/jnc.15879