Latest articles published on Progress in Neurobiology
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 several latest articles published on Progress in Neurobiology.
Title: Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system
Authors: Paulino Ramirez, Gabrielle Zuniga, Wenyan Sun, Adrian Beckmann, Elizabeth Ochoa, Sarah L. DeVos, Bradley Hyman, Gabriel Chiu, Ethan R. Roy, Wei Cao, Miranda Orr, Virginie Buggia-Prevot, William J. Ray, Bess Frost
Type: Original Research Article of Progress in Neurobiology
Highlights
• Retrotransposon transcripts increase in the aging brain and in three mouse models of tauopathy.
• Retrotransposon-encoded protein is elevated in brains of tau transgenic mice.
• DNA copy number of mobile retrotransposons is elevated in brains of tau transgenic mice.
Abstract
Transposable elements comprise almost half of the mammalian genome. A growing body of evidence suggests that transposable element dysregulation accompanies brain aging and neurodegenerative disorders, and that transposable element activation is neurotoxic. Recent studies have identified links between pathogenic forms of tau, a protein that accumulates in Alzheimer’s disease and related “tauopathies,” and transposable element-induced neurotoxicity. Starting with transcriptomic analyses, we find that age- and tau-induced transposable element activation occurs in the mouse brain. Among transposable elements that are activated at the RNA level in the context of brain aging and tauopathy, we find that the endogenous retrovirus (ERV) class of retrotransposons is particularly enriched. We show that protein encoded by Intracisternal A-particle, a highly active mouse ERV, is elevated in brains of tau transgenic mice. Using two complementary approaches, we find that brains of tau transgenic mice contain increased DNA copy number of transposable elements, raising the possibility that these elements actively retrotranspose in the context of tauopathy. Taken together, our study lays the groundwork for future mechanistic studies focused on transposable element regulation in the aging mouse brain and in mouse models of tauopathy and provides support for ongoing therapeutic efforts targeting transposable element activation in patients with Alzheimer’s disease.
Access this article: https://doi.org/10.1016/j.pneurobio.2021.102181
Title: Genetic deletion of α7 nicotinic acetylcholine receptors induces an age-dependent Alzheimer’s disease-like pathology
Authors: Maria Rosaria Tropea, Domenica D. Li Puma, Marcello Melone, Walter Gulisano, Ottavio Arancio, Claudio Grassi, Fiorenzo Conti, Daniela Puzzo
Type: Original Research Article of Progress in Neurobiology
Highlights
• α7nAChR deletion causes an impairment of hippocampal synaptic plasticity and memory in 12-month-old mice.
• α7 KO mice present an age-dependent increase of Amyloid Precursor Protein expression and Aβ levels.
• α7 KO mice at 12 months of age show tau pathology.
• α7 KO mice at 12 months of age show hippocampal neuronal loss and an increase of GFAP-positive astrocytes.
Abstract
The accumulation of amyloid-beta peptide (Aβ) and the failure of cholinergic transmission are key players in Alzheimer’s disease (AD). However, in the healthy brain, Aβ contributes to synaptic plasticity and memory acting through α7 subtype nicotinic acetylcholine receptors (α7nAChRs). Here, we hypothesized that the α7nAChR deletion blocks Aβ physiological function and promotes a compensatory increase in Aβ levels that, in turn, triggers an AD-like pathology.
To validate this hypothesis, we studied the age-dependent phenotype of α7 knock out mice. We found that α7nAChR deletion caused an impairment of hippocampal synaptic plasticity and memory at 12 months of age, paralleled by an increase of Amyloid Precursor Protein expression and Aβ levels. This was accompanied by other classical AD features such as a hyperphosphorylation of tau at residues Ser 199, Ser 396, Thr 205, a decrease of GSK-3β at Ser 9, the presence of paired helical filaments and neurofibrillary tangles, neuronal loss and an increase of GFAP-positive astrocytes.
Our findings suggest that α7nAChR malfunction might precede Aβ and tau pathology, offering a different perspective to interpret the failure of anti-Aβ therapies against AD and to find novel therapeutical approaches aimed at restoring α7nAChRs-mediated Aβ function at the synapse.
Access this article: https://doi.org/10.1016/j.pneurobio.2021.102154
Title: The role of Extracellular Vesicles during CNS development
Authors: Nasim Bahram Sangani, Ana Rita Gomes, Leopold M.G. Curfs, Chris P. Reutelingsperger
Type: Original Research Article of Progress in Neurobiology
Highlights
• Neuronal and non-neuronal cells release Extracellular Vesicles (EVs) to exchange information within the Central Nervous System (CNS).
• EVs contribute to normal brain development from neurogenesis to myelination and beyond.
• EVs can serve as biomarkers for screening developmental abnormalities and therefore can offer early intervention for neurodevelopmental disorders.
Abstract:
With a diverse set of neuronal and glial cell populations, Central Nervous System (CNS) has one of the most complex structures in the body. Intercellular communication is therefore highly important to coordinate cell-to-cell interactions. Besides electrical and chemical messengers, CNS cells also benefit from another communication route, what is known as extracellular vesicles, to harmonize their interactions. Extracellular Vesicles (EVs) and their subtype exosomes are membranous particles secreted by cells and contain information packaged in the form of biomolecules such as small fragments of DNA, lipids, miRNAs, mRNAs, and proteins. They are able to efficiently drive changes upon their arrival to recipient cells. EVs actively participate in all stages of CNS development by stimulating neural cell proliferation, differentiation, synaptic formation, and mediating reciprocal interactions between neurons and oligodendrocyte for myelination process. The aim of the present review is to enlighten the presence and contribution of EVs at each CNS developmental milestone.
Access this article: https://doi.org/10.1016/j.pneurobio.2021.102124
Title: DJ-1 in neurodegenerative diseases: Pathogenesis and clinical application
Authors: Maoxin Huang, Shengdi Chen
Type: Review Article of Progress in Neurobiology
Highlights:
• In Parkinson’s disease (PD), PARK7 mutations, aberrant expression, abnormal posttranslational modifications, etc., are key upstream factors of DJ-1 abnormalities. DJ-1 abnormalities consequently led to nigral dopaminergic neurodegeneration through triggering multiple downstream pathologic pathways.
• The upstream factors of DJ-1 abnormalities observed in PD were also present in other neurodegenerative diseases. The downstream pathologic pathways of DJ-1 abnormalities observed in PD are actually common pathogeneses of neurodegeneration shared by most neurodegenerative diseases.
• The roles of DJ-1 in Alzheimer’s disease, amyotrophic lateral sclerosis and Huntington's disease have been preliminarily studied, revealing the essential implication of DJ-1 in these diseases.
• DJ-1 has been extensively studied as a potential biomarker and a therapeutic target for PD as well as other neurodegenerative diseases.
Abstract:
Neurodegenerative diseases (NDs) are one of the major health threats to human characterized by selective and progressive neuronal loss. The mechanisms of NDs are still not fully understood. The study of genetic defects and disease-related proteins offers us a window into the mystery of it, and the extension of knowledge indicates that different NDs share similar features, mechanisms, and even genetic or protein abnormalities. Among these findings, PARK7 and its production DJ-1 protein, which was initially found implicated in PD, have also been found altered in other NDs. PARK7 mutations, altered expression and posttranslational modification (PTM) cause DJ-1 abnormalities, which in turn lead to downstream mechanisms shared by most NDs, such as mitochondrial dysfunction, oxidative stress, protein aggregation, autophagy defects, and so on. The knowledge of DJ-1 derived from PD researches might apply to other NDs in both basic research and clinical application, and might yield novel insights into and alternative approaches for dealing with NDs.
Access this article: https://doi.org/10.1016/j.pneurobio.2021.102114
Title: Dysfunction of X-linked inhibitor of apoptosis protein (XIAP) triggers neuropathological processes via altered p53 activity in Huntington’s disease
Authors: Seung Jae Hyeon, Jinyoung Park, Junsang Yoo, Su-Hyun Kim, Yu Jin Hwang, Seung-Chan Kim, Tian Liu, Hyun Soo Shim, Yunha Kim, Yakdol Cho, Jiwan Woo, Key-Sun Kim, Richard H. Myers, Hannah L. Ryu, Neil W. Kowall, Eun Joo Song, Eun Mi Hwang, Hyemyung Seo, Junghee Lee, Hoon Ryu
Type: Original Research Article of Progress in Neurobiology
Abstract:
• This study found a new molecular mechanism that XIAP directly interacts with p53 and modulates p53 stability in medium spiny neuons.
• XIAP modulates the turnover of p53 via autophagy pathway.
• XIAP dysfunction leads to abnormal increase of p53 activity, mitochondrial dysfunction, and striatal neuron damage in HD.
• XIAP-p53 pathway can be a novel pathological marker and a therapeutic target in the pathogenesis of HD.
Highlights:
Mitochondrial dysfunction is associated with neuronal damage in Huntington’s disease (HD), but the precise mechanism of mitochondria-dependent pathogenesis is not understood yet. Herein, we found that colocalization of XIAP and p53 was prominent in the cytosolic compartments of normal subjects but reduced in HD patients and HD transgenic animal models. Overexpression of mutant Huntingtin (mHTT) reduced XIAP levels and elevated mitochondrial localization of p53 in striatal cells in vitro and in vivo. Interestingly, XIAP interacted directly with the C-terminal domain of p53 and decreased its stability via autophagy. Overexpression of XIAP prevented mitochondrially targeted-p53 (Mito-p53)-induced mitochondrial oxidative stress and striatal cell death, whereas, knockdown of XIAP exacerbated Mito-p53-induced neuronal damage in vitro. In vivo transduction of AAV-shRNA XIAP in the dorsal striatum induced rapid onset of disease and reduced the lifespan of HD transgenic (N171-82Q) mice compared to WT littermate mice. XIAP dysfunction led to ultrastructural changes of the mitochondrial cristae and nucleus morphology in striatal cells. Knockdown of XIAP exacerbated neuropathology and motor dysfunctions in N171-82Q mice. In contrast, XIAP overexpression improved neuropathology and motor behaviors in both AAV-mHTT-transduced mice and N171-82Q mice. Our data provides a molecular and pathological mechanism that deregulation of XIAP triggers mitochondria dysfunction and other neuropathological processes via the neurotoxic effect of p53 in HD. Together, the XIAP-p53 pathway is a novel pathological marker and can be a therapeutic target for improving the symptoms in HD.
Access this article: https://doi.org/10.1016/j.pneurobio.2021.102110
Title: Autophagy as a gateway for the effects of methamphetamine: From neurotransmitter release and synaptic plasticity to psychiatric and neurodegenerative disorders
Authors: Fiona Limanaqi, Carla L. Busceti, Roberta Celli, Francesca Biagioni, Francesco Fornai
Type: Review Article of Progress in Neurobiology
Highlights:
• Autophagy modulates neurotransmitter release, synaptic plasticity, and neuronal survival.
• METH impairs the autophagy machinery by altering LC3 compartmentalization.
• Autophagy impairment fosters abnormal DA transmission and proteinopathy.
• METH-induced autophagy impairment fosters maladaptive plasticity and neurotoxicity.
• Autophagy bridges drug abuse, psychiatric manifestations, and neurodegenerative phenomena.
Abstract:
As a major eukaryotic cell clearing machinery, autophagy grants cell proteostasis, which is key for neurotransmitter release, synaptic plasticity, and neuronal survival. In line with this, besides neuropathological events, autophagy dysfunctions are bound to synaptic alterations that occur in mental disorders, and early on, in neurodegenerative diseases. This is also the case of methamphetamine (METH) abuse, which leads to psychiatric disturbances and neurotoxicity. While consistently altering the autophagy machinery, METH produces behavioral and neurotoxic effects through molecular and biochemical events that can be recapitulated by autophagy blockade. These consist of altered physiological dopamine (DA) release, abnormal stimulation of DA and glutamate receptors, as well as oxidative, excitotoxic, and neuroinflammatory events. Recent molecular insights suggest that METH early impairs the autophagy machinery, though its functional significance remains to be investigated. Here we discuss evidence suggesting that alterations of DA transmission and autophagy are intermingled within a chain of events underlying behavioral alterations and neurodegenerative phenomena produced by METH. Understanding how METH alters the autophagy machinery is expected to provide novel insights into the neurobiology of METH addiction sharing some features with psychiatric disorders and parkinsonism.
Access this article: https://doi.org/10.1016/j.pneurobio.2021.102112
