and

Hot Keywords
Ageing Neurodegenerative Diseases Neurodegeneration AD

Top

Several latest articles published on Communications Biology

Published on: 21 Jul 2021 Viewed: 493

Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series. This week, we would like to share 5 latest articles on neurodegenerative diseases.

Title: Essential roles of plexin-B3+ oligodendrocyte precursor cells in the pathogenesis of Alzheimer’s disease
Authors: Naomi Nihonmatsu-Kikuchi, Xiu-Jun Yu, Yoshiki Matsuda, Nobuyuki Ozawa, Taeko Ito, Kazuhito Satou, Tadashi Kaname, Yasushi Iwasaki, Akio Akagi, Mari Yoshida, Shuta Toru, Katsuiku Hirokawa, Akihiko Takashima, Masato Hasegawa, Toshiki Uchihara, Yoshitaka Tatebayashi
Type: Article from Communications Biology
Abstract:
The role of oligodendrocyte lineage cells, the largest glial population in the adult central nervous system (CNS), in the pathogenesis of Alzheimer’s disease (AD) remains elusive. Here, we developed a culture method for adult oligodendrocyte progenitor cells (aOPCs). Fibroblast growth factor 2 (FGF2) promotes survival and proliferation of NG2+ aOPCs in a serum-free defined medium; a subpopulation (~5%) of plexin-B3+ aOPCs was also found. FGF2 withdrawal decreased NG2+, but increased plexin-B3+ aOPCs and Aβ1-42 secretion. Plexin-B3+ aOPCs were distributed throughout the adult rat brain, although less densely than NG2+ aOPCs. Spreading depolarization induced delayed cortical plexin-B3+ aOPC gliosis in the ipsilateral remote cortex. Furthermore, extracellular Aβ1-42 accumulation was occasionally found around plexin-B3+ aOPCs near the lesions. In AD brains, virtually all cortical SPs were immunostained for plexin-B3, and plexin-B3 levels increased significantly in the Sarkosyl-soluble fractions. These findings suggest that plexin-B3+ aOPCs may play essential roles in AD pathogenesis, as natural Aβ-secreting cells.
Access this article: https://doi.org/10.1038/s42003-021-02404-7


Title: Cryo-electron tomography provides topological insights into mutant huntingtin exon 1 and polyQ aggregates
Authors: Jesús G. Galaz-Montoya, Sarah H. Shahmoradian, Koning Shen, Judith Frydman, Wah Chiu
Type: Article from Communications Biology
Abstract:
Huntington disease (HD) is a neurodegenerative trinucleotide repeat disorder caused by an expanded poly-glutamine (polyQ) tract in the mutant huntingtin (mHTT) protein. The formation and topology of filamentous mHTT inclusions in the brain (hallmarks of HD implicated in neurotoxicity) remain elusive. Using cryo-electron tomography and subtomogram averaging, here we show that mHTT exon 1 and polyQ-only aggregates in vitro are structurally heterogenous and filamentous, similar to prior observations with other methods. Yet, we find filaments in both types of aggregates under ~2 nm in width, thinner than previously reported, and regions forming large sheets. In addition, our data show a prevalent subpopulation of filaments exhibiting a lumpy slab morphology in both aggregates, supportive of the polyQ core model. This provides a basis for future cryoET studies of various aggregated mHTT and polyQ constructs to improve their structure-based modeling as well as their identification in cells without fusion tags.
Access this article: https://doi.org/10.1038/s42003-021-02360-2


Title: Two human metabolites rescue a C. elegans model of Alzheimer’s disease via a cytosolic unfolded protein response
Authors: Priyanka Joshi, Michele Perni, Ryan Limbocker, Benedetta Mannini, Sam Casford, Sean Chia, Johnny Habchi, Johnathan Labbadia, Christopher M. Dobson, Michele Vendruscolo
Type: Article from Communications Biology
Abstract:
Age-related changes in cellular metabolism can affect brain homeostasis, creating conditions that are permissive to the onset and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Although the roles of metabolites have been extensively studied with regard to cellular signaling pathways, their effects on protein aggregation remain relatively unexplored. By computationally analysing the Human Metabolome Database, we identified two endogenous metabolites, carnosine and kynurenic acid, that inhibit the aggregation of the amyloid beta peptide (Aβ) and rescue a C. elegans model of Alzheimer’s disease. We found that these metabolites act by triggering a cytosolic unfolded protein response through the transcription factor HSF-1 and downstream chaperones HSP40/J-proteins DNJ-12 and DNJ-19. These results help rationalise previous observations regarding the possible anti-ageing benefits of these metabolites by providing a mechanism for their action. Taken together, our findings provide a link between metabolite homeostasis and protein homeostasis, which could inspire preventative interventions against neurodegenerative disorders.
Access this article: https://doi.org/10.1038/s42003-021-02218-7


Title: Age-dependent shift in the de novo proteome accompanies pathogenesis in an Alzheimer’s disease mouse model
Authors: Megan K. Elder, Hediye Erdjument-Bromage, Mauricio M. Oliveira, Maggie Mamcarz, Thomas A. Neubert, Eric Klann
Type: Article from Communications Biology
Abstract:
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder associated with memory loss, but the AD-associated neuropathological changes begin years before memory impairments. Investigation of the early molecular abnormalities in AD might offer innovative opportunities to target memory impairment prior to onset. Decreased protein synthesis plays a fundamental role in AD, yet the consequences of this dysregulation for cellular function remain unknown. We hypothesize that alterations in the de novo proteome drive early metabolic alterations in the hippocampus that persist throughout AD progression. Using a combinatorial amino acid tagging approach to selectively label and enrich newly synthesized proteins, we found that the de novo proteome is disturbed in young APP/PS1 mice prior to symptom onset, affecting the synthesis of multiple components of the synaptic, lysosomal, and mitochondrial pathways. Furthermore, the synthesis of large clusters of ribosomal subunits were affected throughout development. Our data suggest that large-scale changes in protein synthesis could underlie cellular dysfunction in AD.
Access this article: https://doi.org/10.1038/s42003-021-02324-6


Title: Precise CAG repeat contraction in a Huntington’s Disease mouse model is enabled by gene editing with SpCas9-NG
Authors: Seiya Oura, Taichi Noda, Naoko Morimura, Seiji Hitoshi, Hiroshi Nishimasu, Yoshitaka Nagai, Osamu Nureki, Masahito Ikawa
Type: Article from Communications Biology
Abstract:
The clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 system is a research hotspot in gene therapy. However, the widely used Streptococcus pyogenes Cas9 (WT-SpCas9) requires an NGG protospacer adjacent motif (PAM) for target recognition, thereby restricting targetable disease mutations. To address this issue, we recently reported an engineered SpCas9 nuclease variant (SpCas9-NG) recognizing NGN PAMs. Here, as a feasibility study, we report SpCas9-NG-mediated repair of the abnormally expanded CAG repeat tract in Huntington’s disease (HD). By targeting the boundary of CAG repeats with SpCas9-NG, we precisely contracted the repeat tracts in HD-mouse-derived embryonic stem (ES) cells. Further, we confirmed the recovery of phenotypic abnormalities in differentiated neurons and animals produced from repaired ES cells. Our study shows that SpCas9-NG can be a powerful tool for repairing abnormally expanded CAG repeats as well as other disease mutations that are difficult to access with WT-SpCas9.
Access this article: https://doi.org/10.1038/s42003-021-02304-w

© 2016-2023 OAE Publishing Inc., except certain content provided by third parties