bims-metalz 2023-11-12 papers

Issue of 2023–11–12
six papers selected by
Mikaila Chetty, Goa University

Mol Neurodegener. 2023 Nov 10. 18(1): 82

Simple model systems reveal conserved mechanisms of Alzheimer's disease and related tauopathies.

The lack of effective therapies that slow the progression of Alzheimer's disease (AD) and related tauopathies highlights the need for a more comprehensive understanding of the fundamental cellular mechanisms underlying these diseases. Model organisms, including yeast, worms, and flies, provide simple systems with which to investigate the mechanisms of disease. The evolutionary conservation of cellular pathways regulating proteostasis and stress response in these organisms facilitates the study of genetic factors that contribute to, or protect against, neurodegeneration. Here, we review genetic modifiers of neurodegeneration and related cellular pathways identified in the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster, focusing on models of AD and related tauopathies. We further address the potential of simple model systems to better understand the fundamental mechanisms that lead to AD and other neurodegenerative disorders.

Keywords: Aggregation; Alzheimer’s disease; Amyloid-β; C. elegans; Cellular pathways; Drosophila; Genetic modifiers; Neurodegeneration; S. cerevisiae; Tau; Tauopathy

DOI: https://doi.org/10.1186/s13024-023-00664-x

Nat Aging. 2023 Nov 09.

Chiral nanoparticle-remodeled gut microbiota alleviates neurodegeneration via the gut-brain axis.

Xiao Guo, Chen Li, Jia Zhang, Maozhong Sun, Jun Xu, Chuanlai Xu, Hua Kuang, Liguang Xu.

Alzheimer's disease (AD) is characterized by amyloid-β accumulation in the brain and hyperphosphorylated tau aggregation, as well as neuroinflammation. The gut-brain axis has emerged as a therapeutic target in neurodegenerative diseases by modulating metabolic activity, neuroimmune functions and sensory neuronal signaling. Here we investigate interactions between orally ingested chiral Au nanoparticles and the gut microbiota in AD mice. Oral administration of chiral Au nanoparticles restored cognitive abilities and ameliorated amyloid-β and hyperphosphorylated tau pathologies in AD mice via alterations in the gut microbiome composition and an increase in the gut metabolite, indole-3-acetic acid, which was lower in serum and cerebrospinal fluid of patients with AD compared with age-matched controls. Oral administration of indole-3-acetic acid was able to penetrate the blood-brain barrier and alleviated cognitive decline and pathology including neuroinflammation in AD mice. These findings provide a promising therapeutic target for the amelioration of neuroinflammation and treatment of neurodegenerative diseases.

DOI: https://doi.org/10.1038/s43587-023-00516-9

J Parkinsons Dis. 2023 ;13(7): 1079-1106

Pesticides and the Microbiome-Gut-Brain Axis: Convergent Pathways in the Pathogenesis of Parkinson's Disease.

Kristina Kulcsarova, Corinna Bang, Daniela Berg, Eva Schaeffer.

The increasing global burden of Parkinson's disease (PD), termed the PD pandemic, is exceeding expectations related purely to population aging and is likely driven in part by lifestyle changes and environmental factors. Pesticides are well recognized risk factors for PD, supported by both epidemiological and experimental evidence, with multiple detrimental effects beyond dopaminergic neuron damage alone. The microbiome-gut-brain axis has gained much attention in recent years and is considered to be a significant contributor and driver of PD pathogenesis. In this narrative review, we first focus on how both pesticides and the microbiome may influence PD initiation and progression independently, describing pesticide-related central and peripheral neurotoxicity and microbiome-related local and systemic effects due to dysbiosis and microbial metabolites. We then depict the bidirectional interplay between pesticides and the microbiome in the context of PD, synthesizing current knowledge about pesticide-induced dysbiosis, microbiome-mediated alterations in pesticide availability, metabolism and toxicity, and complex systemic pesticide-microbiome-host interactions related to inflammatory and metabolic pathways, insulin resistance and other mechanisms. An overview of the unknowns follows, and the role of pesticide-microbiome interactions in the proposed body-/brain-first phenotypes of PD, the complexity of environmental exposures and gene-environment interactions is discussed. The final part deals with possible further steps for translation, consisting of recommendations on future pesticide use and research as well as an outline of promising preventive/therapeutic approaches targeted on strengthening or restoring a healthy gut microbiome, closing with a summary of current gaps and future perspectives in the field.

Keywords: Parkinson’s disease; Pesticides; alpha-synuclein; gut-brain axis; inflammation; microbiota; short-chain fatty acids

DOI: https://doi.org/10.3233/JPD-230206

Adv Sci (Weinh). 2023 Nov 10. e2307182

APP-C31: An Intracellular Promoter of Both Metal-Free and Metal-Bound Amyloid-β40 Aggregation and Toxicity in Alzheimer's Disease.

Eunju Nam, Yuxi Lin, Jiyong Park, Hyunsu Do, Jiyeon Han, Bohyeon Jeong, Subin Park, Da Yong Lee, Mingeun Kim, Jinju Han, Mu-Hyun Baik, Young-Ho Lee, Mi Hee Lim.

Intracellular C-terminal cleavage of the amyloid precursor protein (APP) is elevated in the brains of Alzheimer's disease (AD) patients and produces a peptide labeled APP-C31 that is suspected to be involved in the pathology of AD. But details about the role of APP-C31 in the development of the disease are not known. Here, this work reports that APP-C31 directly interacts with the N-terminal and self-recognition regions of amyloid-β40 (Aβ40 ) to form transient adducts, which facilitates the aggregation of both metal-free and metal-bound Aβ40 peptides and aggravates their toxicity. Specifically, APP-C31 increases the perinuclear and intranuclear generation of large Aβ40 deposits and, consequently, damages the nucleus leading to apoptosis. The Aβ40 -induced degeneration of neurites and inflammation are also intensified by APP-C31 in human neurons and murine brains. This study demonstrates a new function of APP-C31 as an intracellular promoter of Aβ40 amyloidogenesis in both metal-free and metal-present environments, and may offer an interesting alternative target for developing treatments for AD that have not been considered thus far.

Keywords: accelerator toward amyloidogenesis; amyloid precursor protein; amyloid-β; metal ions; protein-protein interaction

DOI: https://doi.org/10.1002/advs.202307182

FASEB Bioadv. 2023 Nov;5(11): 484-505

Human wild-type and D76N β2-microglobulin variants are significant proteotoxic and metabolic stressors for transgenic C. elegans.

Sara Raimondi, Giulia Faravelli, Paola Nocerino, Valentina Mondani, Alma Baruffaldi, Loredana Marchese, Maria Chiara Mimmi, Diana Canetti, Guglielmo Verona, Marianna Caterino, Margherita Ruoppolo, P Patrizia Mangione, Vittorio Bellotti, Francesca Lavatelli, Sofia Giorgetti.

β2-microglobulin (β2-m) is a plasma protein derived from physiological shedding of the class I major histocompatibility complex (MHCI), causing human systemic amyloidosis either due to persistently high concentrations of the wild-type (WT) protein in hemodialyzed patients, or in presence of mutations, such as D76N β2-m, which favor protein deposition in the adulthood, despite normal plasma levels. Here we describe a new transgenic Caenorhabditis elegans (C. elegans) strain expressing human WT β2-m at high concentrations, mimicking the condition that underlies dialysis-related amyloidosis (DRA) and we compare it to a previously established strain expressing the highly amyloidogenic D76N β2-m at lower concentrations. Both strains exhibit behavioral defects, the severity of which correlates with β2-m levels rather than with the presence of mutations, being more pronounced in WT β2-m worms. β2-m expression also has a deep impact on the nematodes' proteomic and metabolic profiles. Most significantly affected processes include protein degradation and stress response, amino acids metabolism, and bioenergetics. Molecular alterations are more pronounced in worms expressing WT β2-m at high concentration compared to D76N β2-m worms. Altogether, these data show that β2-m is a proteotoxic protein in vivo also in its wild-type form, and that concentration plays a key role in modulating pathogenicity. Our transgenic nematodes recapitulate the distinctive features subtending DRA compared to hereditary β2-m amyloidosis (high levels of non-mutated β2-m vs. normal levels of variant β2-m) and provide important clues on the molecular bases of these human diseases.

Keywords: C. elegans; integrated omics; misfolding; proteotoxicity; systemic amyloidosis; β2‐microglobulin

DOI: https://doi.org/10.1096/fba.2023-00073

Neuron. 2023 Nov 02. pii: S0896-6273(23)00756-0. [Epub ahead of print]

The neuropeptidergic connectome of C. elegans.

Lidia Ripoll-Sánchez, Jan Watteyne, HaoSheng Sun, Robert Fernandez, Seth R Taylor, Alexis Weinreb, Barry L Bentley, Marc Hammarlund, David M Miller, Oliver Hobert, Isabel Beets, Petra E Vértes, William R Schafer.

Efforts are ongoing to map synaptic wiring diagrams, or connectomes, to understand the neural basis of brain function. However, chemical synapses represent only one type of functionally important neuronal connection; in particular, extrasynaptic, "wireless" signaling by neuropeptides is widespread and plays essential roles in all nervous systems. By integrating single-cell anatomical and gene-expression datasets with biochemical analysis of receptor-ligand interactions, we have generated a draft connectome of neuropeptide signaling in the C. elegans nervous system. This network is characterized by high connection density, extended signaling cascades, autocrine foci, and a decentralized topology, with a large, highly interconnected core containing three constituent communities sharing similar patterns of input connectivity. Intriguingly, several key network hubs are little-studied neurons that appear specialized for peptidergic neuromodulation. We anticipate that the C. elegans neuropeptidergic connectome will serve as a prototype to understand how networks of neuromodulatory signaling are organized.

Keywords: C. elegans; connectomics; networks; neuromodulation; neuropeptides

DOI: https://doi.org/10.1016/j.neuron.2023.09.043