International Journal of Molecular Sciences

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39 pages, 2048 KiB

Open AccessReview

The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases

by Sina Shadfar, Mariana Brocardo and Julie D. Atkin

Int. J. Mol. Sci. 2022, 23(5), 2484; https://doi.org/10.3390/ijms23052484 - 24 Feb 2022

Cited by 22 | Viewed by 6202

Abstract

Human cells are exposed to numerous exogenous and endogenous insults every day. Unlike other molecules, DNA cannot be replaced by resynthesis, hence damage to DNA can have major consequences for the cell. The DNA damage response contains overlapping signalling networks that repair DNA [...] Read more.

Human cells are exposed to numerous exogenous and endogenous insults every day. Unlike other molecules, DNA cannot be replaced by resynthesis, hence damage to DNA can have major consequences for the cell. The DNA damage response contains overlapping signalling networks that repair DNA and hence maintain genomic integrity, and aberrant DNA damage responses are increasingly described in neurodegenerative diseases. Furthermore, DNA repair declines during aging, which is the biggest risk factor for these conditions. If unrepaired, the accumulation of DNA damage results in death to eliminate cells with defective genomes. This is particularly important for postmitotic neurons because they have a limited capacity to proliferate, thus they must be maintained for life. Neuronal death is thus an important process in neurodegenerative disorders. In addition, the inability of neurons to divide renders them susceptible to senescence or re-entry to the cell cycle. The field of cell death has expanded significantly in recent years, and many new mechanisms have been described in various cell types, including neurons. Several of these mechanisms are linked to DNA damage. In this review, we provide an overview of the cell death pathways induced by DNA damage that are relevant to neurons and discuss the possible involvement of these mechanisms in neurodegenerative conditions. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuronal Death in Neurodegeneration)

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11 pages, 729 KiB

Open AccessReview

Beyond HAT Adaptor: TRRAP Liaisons with Sp1-Mediated Transcription

by Bo-Kun Yin and Zhao-Qi Wang

Int. J. Mol. Sci. 2021, 22(22), 12445; https://doi.org/10.3390/ijms222212445 - 18 Nov 2021

Cited by 10 | Viewed by 2766

Abstract

The members of the phosphatidylinositol 3-kinase-related kinase (PIKK) family play vital roles in multiple biological processes, including DNA damage response, metabolism, cell growth, mRNA decay, and transcription. TRRAP, as the only member lacking the enzymatic activity in this family, is an adaptor protein [...] Read more.

The members of the phosphatidylinositol 3-kinase-related kinase (PIKK) family play vital roles in multiple biological processes, including DNA damage response, metabolism, cell growth, mRNA decay, and transcription. TRRAP, as the only member lacking the enzymatic activity in this family, is an adaptor protein for several histone acetyltransferase (HAT) complexes and a scaffold protein for multiple transcription factors. TRRAP has been demonstrated to regulate various cellular functions in cell cycle progression, cell stemness maintenance and differentiation, as well as neural homeostasis. TRRAP is known to be an important orchestrator of many molecular machineries in gene transcription by modulating the activity of some key transcription factors, including E2F1, c-Myc, p53, and recently, Sp1. This review summarizes the biological and biochemical studies on the action mode of TRRAP together with the transcription factors, focusing on how TRRAP-HAT mediates the transactivation of Sp1-governing biological processes, including neurodegeneration. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuronal Death in Neurodegeneration)

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9 pages, 1046 KiB

Open AccessBrief Report

Zooming into Gut Dysbiosis in Parkinson’s Disease: New Insights from Functional Mapping

by Luigia Turco, Nicola Opallo, Elisabetta Buommino, Carmen De Caro, Claudio Pirozzi, Giuseppina Mattace Raso, Francesca Lembo and Lorena Coretti

Int. J. Mol. Sci. 2023, 24(11), 9777; https://doi.org/10.3390/ijms24119777 - 5 Jun 2023

Cited by 1 | Viewed by 1326

Abstract

Gut dysbiosis has been involved in the pathogenesis and progression of Parkinson’s disease (PD), but the mechanisms through which gut microbiota (GM) exerts its influences deserve further study. Recently, we proposed a two-hit mouse model of PD in which ceftriaxone (CFX)-induced dysbiosis amplifies [...] Read more.

Gut dysbiosis has been involved in the pathogenesis and progression of Parkinson’s disease (PD), but the mechanisms through which gut microbiota (GM) exerts its influences deserve further study. Recently, we proposed a two-hit mouse model of PD in which ceftriaxone (CFX)-induced dysbiosis amplifies the neurodegenerative phenotype generated by striatal 6-hydroxydopamine (6-OHDA) injection in mice. Low GM diversity and the depletion of key gut colonizers and butyrate producers were the main signatures of GM alteration in this model. Here, we used the phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt2) to unravel candidate pathways of cell-to-cell communication associated with dual-hit mice and potentially involved in PD progression. We focused our analysis on short-chain fatty acids (SCFAs) metabolism and quorum sensing (QS) signaling. Based on linear discriminant analysis, combined with the effect size results, we found increased functions linked to pyruvate utilization and a depletion of acetate and butyrate production in 6-OHDA+CFX mice. The specific arrangement of QS signaling as a possible result of the disrupted GM structure was also observed. With this exploratory study, we suggested a scenario in which SCFAs metabolism and QS signaling might represent the effectors of gut dysbiosis potentially involved in the designation of the functional outcomes that contribute to the exacerbation of the neurodegenerative phenotype in the dual-hit animal model of PD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuronal Death in Neurodegeneration)

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