bims-proned 2023-09-24 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2023–09–24
seven papers selected by
Verena Kohler, University of Graz

Phase separation and pathologic transitions of RNP condensates in neurons: implications for amyotrophic lateral sclerosis, frontotemporal dementia and other neurodegenerative disorders.
Investigating the potential effects of α-synuclein aggregation on susceptibility to chronic stress in a mouse Parkinson's disease model.
Removal of extracellular human amyloid beta aggregates by extracellular proteases in C. elegans.
Conformational inhibitors of protein aggregation.
Cogs in the autophagic machine-equipped to combat dementia-prone neurodegenerative diseases.
Metabolic deregulation associated with aging modulates protein aggregation in the yeast model of Huntington's disease.
Stress granule-mediated RNA regulatory mechanism in Alzheimer's disease.

Front Mol Neurosci. 2023 ;16 1242925

Phase separation and pathologic transitions of RNP condensates in neurons: implications for amyotrophic lateral sclerosis, frontotemporal dementia and other neurodegenerative disorders.

Aditi Naskar, Asima Nayak, Muthu Raj Salaikumaran, Sonali S Vishal, Pallavi P Gopal.

  Liquid-liquid phase separation results in the formation of dynamic biomolecular condensates, also known as membrane-less organelles, that allow for the assembly of functional compartments and higher order structures within cells. Multivalent, reversible interactions between RNA-binding proteins (RBPs), including FUS, TDP-43, and hnRNPA1, and/or RNA (e.g., RBP-RBP, RBP-RNA, RNA-RNA), result in the formation of ribonucleoprotein (RNP) condensates, which are critical for RNA processing, mRNA transport, stability, stress granule assembly, and translation. Stress granules, neuronal transport granules, and processing bodies are examples of cytoplasmic RNP condensates, while the nucleolus and Cajal bodies are representative nuclear RNP condensates. In neurons, RNP condensates promote long-range mRNA transport and local translation in the dendrites and axon, and are essential for spatiotemporal regulation of gene expression, axonal integrity and synaptic function. Mutations of RBPs and/or pathologic mislocalization and aggregation of RBPs are hallmarks of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease. ALS/FTD-linked mutations of RBPs alter the strength and reversibility of multivalent interactions with other RBPs and RNAs, resulting in aberrant phase transitions. These aberrant RNP condensates have detrimental functional consequences on mRNA stability, localization, and translation, and ultimately lead to compromised axonal integrity and synaptic function in disease. Pathogenic protein aggregation is dependent on various factors, and aberrant dynamically arrested RNP condensates may serve as an initial nucleation step for pathologic aggregate formation. Recent studies have focused on identifying mechanisms by which neurons resolve phase transitioned condensates to prevent the formation of pathogenic inclusions/aggregates. The present review focuses on the phase separation of neurodegenerative disease-linked RBPs, physiological functions of RNP condensates, and the pathologic role of aberrant phase transitions in neurodegenerative disease, particularly ALS/FTD. We also examine cellular mechanisms that contribute to the resolution of aberrant condensates in neurons, and potential therapeutic approaches to resolve aberrantly phase transitioned condensates at a molecular level.

Keywords:  RNA-binding proteins; aggregation; biomolecular condensates; neurodegenerative disease; phase separation

DOI:  https://doi.org/10.3389/fnmol.2023.1242925
Pharmacol Rep. 2023 Sep 19.

Investigating the potential effects of α-synuclein aggregation on susceptibility to chronic stress in a mouse Parkinson's disease model.

Anna Alwani, Katarzyna Maziarz, Gabriela Burda, Monika Jankowska-Kiełtyka, Adam Roman, Gabriela Łyszczarz, Safak Er, Justyna Barut, Olga Barczyk-Woźnicka, Elżbieta Pyza, Grzegorz Kreiner, Irena Nalepa, Piotr Chmielarz.

   BACKGROUND: Parkinson's disease (PD) is a motor disorder characterized by the degeneration of dopaminergic neurons, putatively due to the accumulation of α-synuclein (α-syn) in Lewy bodies (LBs) in Substantia Nigra. PD is also associated with the formation of LBs in brain areas responsible for emotional and cognitive regulation such as the amygdala and prefrontal cortex, and concurrent depression prevalence in PD patients. The exact link between dopaminergic cell loss, α-syn aggregation, depression, and stress, a major depression risk factor, is unclear. Therefore, we aimed to explore the interplay between sensitivity to chronic stress and α-syn aggregation.
METHODS: Bilateral injections of α-syn preformed fibrils (PFFs) into the striatum of C57Bl/6 J mice were used to induce α-syn aggregation. Three months after injections, animals were exposed to chronic social defeat stress.
RESULTS: α-syn aggregation did not affect stress susceptibility but independently caused increased locomotor activity in the open field test, reduced anxiety in the light-dark box test, and increased active time in the tail suspension test. Ex vivo analysis revealed modest dopaminergic neuron loss in the substantia nigra and reduced dopaminergic innervation in the dorsal striatum in PFFs injected groups. α-Syn aggregates were prominent in the amygdala, prefrontal cortex, and substantia nigra, with minimal α-syn aggregation in the raphe nuclei and locus coeruleus.
CONCLUSIONS: Progressive bilateral α-syn aggregation might lead to compensatory activity increase and alterations in emotionally regulated behavior, without affecting stress susceptibility. Understanding how α-syn aggregation and degeneration in specific brain structures contribute to depression and anxiety in PD patients requires further investigation.

Keywords:  Chronic stress; Depression; Non-motor symptoms; Parkinson’s disease; Preformed fibrils; α-synuclein

DOI:  https://doi.org/10.1007/s43440-023-00530-z
Elife. 2023 Sep 20. pii: e83465. [Epub ahead of print]12

Removal of extracellular human amyloid beta aggregates by extracellular proteases in C. elegans.

Elisabeth Jongsma, Anita Goyala, José Maria Mateos, Collin Yvès Ewald.

  The amyloid-beta (Aβ) plaques found in Alzheimer's disease (AD) patients' brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence Aβ aggregate formation, yet their role in clearance is unknown. To investigate the potential role of collagens in forming and clearance of extracellular aggregates in vivo, we created a transgenic Caenorhabditis elegans strain that expresses and secretes human Aβ1-42. This secreted Aβ forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human Aβ aggregation regulators, we identified different collagens to ameliorate or potentiate Aβ aggregation. We show that a disintegrin and metalloprotease ADM-2, an orthologue of ADAM9, reduces the load of extracellular Aβ aggregates. ADM-2 is required and sufficient to remove the extracellular Aβ aggregates. Thus, we provide in-vivo evidence of collagens essential for aggregate formation and metalloprotease participating in extracellular Aβ aggregate removal.

Keywords:  C. elegans; cell biology; neuroscience

DOI:  https://doi.org/10.7554/eLife.83465
Curr Opin Struct Biol. 2023 Sep 15. pii: S0959-440X(23)00174-4. [Epub ahead of print]83 102700

Conformational inhibitors of protein aggregation.

María Del Carmen Fernández Ramírez, Shumaila Afrin, Lorena Saelices.

  Amyloidoses are fatal conditions associated with the aggregation of proteins into amyloid fibrils that deposit systemically and/or locally. Possibly because the causal mechanism of protein aggregation and deposition is not fully understood, this group of diseases remains uncurable. Advances in structural biology, such as the use of nuclear magnetic resonance and cryo-electron microscopy, have enabled the study of the structures and the conformational nature of the proteins whose aggregation is associated with the underlying pathogenesis of amyloidosis. As a result, the last years of research have translated into the development of directed therapeutic strategies that target the specific conformations of precursors, fibrils, and intermediary species. Current efforts include the use of small molecules, peptides, and antibodies. This review summarizes the recent progress in developing strategies that target specific protein conformations for the treatment of amyloidoses.

Keywords:  Amyloid; Amyloidosis; Conformational inhibitors; Protein aggregation

DOI:  https://doi.org/10.1016/j.sbi.2023.102700
Front Mol Neurosci. 2023 ;16 1225227

Cogs in the autophagic machine-equipped to combat dementia-prone neurodegenerative diseases.

Sholto de Wet, Rensu Theart, Ben Loos.

  Neurodegenerative diseases are often characterized by hydrophobic inclusion bodies, and it may be the case that the aggregate-prone proteins that comprise these inclusion bodies are in fact the cause of neurotoxicity. Indeed, the appearance of protein aggregates leads to a proteostatic imbalance that causes various interruptions in physiological cellular processes, including lysosomal and mitochondrial dysfunction, as well as break down in calcium homeostasis. Oftentimes the approach to counteract proteotoxicity is taken to merely upregulate autophagy, measured by an increase in autophagosomes, without a deeper assessment of contributors toward effective turnover through autophagy. There are various ways in which autophagy is regulated ranging from the mammalian target of rapamycin (mTOR) to acetylation status of proteins. Healthy mitochondria and the intracellular energetic charge they preserve are key for the acidification status of lysosomes and thus ensuring effective clearance of components through the autophagy pathway. Both mitochondria and lysosomes have been shown to bear functional protein complexes that aid in the regulation of autophagy. Indeed, it may be the case that minimizing the proteins associated with the respective neurodegenerative pathology may be of greater importance than addressing molecularly their resulting inclusion bodies. It is in this context that this review will dissect the autophagy signaling pathway, its control and the manner in which it is molecularly and functionally connected with the mitochondrial and lysosomal system, as well as provide a summary of the role of autophagy dysfunction in driving neurodegenerative disease as a means to better position the potential of rapamycin-mediated bioactivities to control autophagy favorably.

Keywords:  autophagy; lysosomes; mitochondrial function; mitophagy; neurodegenerative diseases; proteostasis

DOI:  https://doi.org/10.3389/fnmol.2023.1225227
J Biomol Struct Dyn. 2023 Sep 21. 1-18

Metabolic deregulation associated with aging modulates protein aggregation in the yeast model of Huntington's disease.

Sai Sanwid Pradhan, Sai Swaroop R, Sai Phalguna Kanikaram, Datta Darshan V M, Ashish Pargaonkar, Rajesh Babu Dandamudi, Venketesh Sivaramakrishnan.

  Huntington's disease is associated with increased CAG repeat resulting in an expanded polyglutamine tract in the protein Huntingtin (HTT) leading to its aggregation resulting in neurodegeneration. Previous studies have shown that N-terminal HTT with 46Q aggregated in the stationary phase but not the logarithmic phase in the yeast model of HD. We carried out a metabolomic analysis of logarithmic and stationary phase yeast model of HD expressing different polyQ lengths attached to N-terminal HTT tagged with enhanced green fluorescent protein (EGFP). The results show significant changes in the metabolic profile and deregulated pathways in stationary phase cells compared to logarithmic phase cells. Comparison of metabolic pathways obtained from logarithmic phase 46Q versus 25Q with those obtained for presymptomatic HD patients from our previous study and drosophila model of HD showed considerable overlap. The arginine biosynthesis pathway emerged as one of the key pathways that is common in stationary phase yeast compared to logarithmic phase and HD patients. Treatment of yeast with arginine led to a significant decrease, while transfer to arginine drop-out media led to a significant increase in the size of protein aggregates in both logarithmic and stationary phase yeast model of HD. Knockout of arginine transporters in the endoplasmic reticulum and vacuole led to a significant decrease in mutant HTT aggregation. Overall our results highlight arginine as a critical metabolite that modulates the aggregation of mutant HTT and disease progression in HD.Communicated by Ramaswamy H. Sarma.

Keywords:  Huntingtin; Huntington’s disease; aging; chaperon; metabolomics; neurodegeneration; protein aggregation

DOI:  https://doi.org/10.1080/07391102.2023.2257322
Geriatr Gerontol Int. 2023 Sep 19.

Stress granule-mediated RNA regulatory mechanism in Alzheimer's disease.

Kaoru Sato, Ken-Ichi Takayama, Satoshi Inouei.

  Living organisms experience a range of stresses. To cope effectively with these stresses, eukaryotic cells have evolved a sophisticated mechanism involving the formation of stress granules (SGs), which play a crucial role in protecting various types of RNA species under stress, such as mRNAs and long non-coding RNAs (lncRNAs). SGs are non-membranous cytoplasmic ribonucleoprotein (RNP) granules, and the RNAs they contain are translationally stalled. Importantly, SGs have been thought to contribute to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD). SGs also contain multiple RNA-binding proteins (RBPs), several of which have been implicated in AD progression. SGs are transient structures that dissipate after stress relief. However, the chronic stresses associated with aging lead to the persistent formation of SGs and subsequently to solid-like pathological SGs, which could impair cellular RNA metabolism and also act as a nidus for the aberrant aggregation of AD-associated proteins. In this paper, we provide a comprehensive summary of the physical basis of SG-enriched RNAs and SG-resident RBPs. We then review the characteristics of AD-associated gene transcripts and their similarity to the SG-enriched RNAs. Furthermore, we summarize and discuss the functional implications of SGs in neuronal RNA metabolism and the aberrant aggregation of AD-associated proteins mediated by SG-resident RBPs in the context of AD pathogenesis. Geriatr Gerontol Int 2023; ••: ••-••.

Keywords:  Alzheimer's disease; RNA; RNA-binding protein; neurodegenerative disease; stress granule

DOI:  https://doi.org/10.1111/ggi.14663