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 Trends in Neurosciences.
Title: LRRK2 and idiopathic Parkinson’s disease
Authors: Emily M. Rocha, Matthew T. Keeney, Roberto Di Maio, Briana R. De Miranda, J. Timothy Greenamyre
Type: Review of Trends in Neurosciences
Mutations in LRRK2 that are associated with aberrantly enhanced kinase activity are the most common cause of genetic Parkinson’s disease (PD). Emerging evidence now points to a role of elevated LRRK2 kinase activity without LRRK2 mutations in nongenetic (idiopathic) forms of the disease.
The architecture of LRRK2 influences kinase activation, and enhanced LRRK2 substrate phosphorylation might contribute to PD pathogenesis.
Evidence indicates that LRRK2 kinase activity might be enhanced in idiopathic (i) PD by oxidative stress and/or endolysosomal stress.
Exposure to environmental toxicants linked to iPD by epidemiological studies is also reported to activate LRRK2 kinase activity.
Two therapeutic approaches targeting LRRK2, an antisense oligonucleotide and a kinase inhibitor, are in clinical trials for both carriers of LRRK2 mutations and those with iPD.
The etiology of idiopathic Parkinson’s disease (iPD) is multifactorial, and both genetics and environmental exposures are risk factors. While mutations in leucine-rich repeat kinase-2 (LRRK2) that are associated with increased kinase activity are the most common cause of autosomal dominant PD, the role of LRRK2 in iPD, independent of mutations, remains uncertain. In this review, we discuss how the architecture of LRRK2 influences kinase activation and how enhanced LRRK2 substrate phosphorylation might contribute to pathogenesis. We describe how oxidative stress and endolysosomal dysfunction, both of which occur in iPD, can activate non-mutated LRRK2 to a similar degree as pathogenic mutations. Similarly, environmental toxicants that are linked epidemiologically to iPD risk can also activate LRRK2. In aggregate, current evidence suggests an important role for LRRK2 in iPD.
Access this article: https://doi.org/10.1016/j.tins.2021.12.002
Title: Beneficial and detrimental functions of microglia during viral encephalitis
Authors: Inken Waltl, Ulrich Kalinke
Type: Review of Trends in Neurosciences
During homeostasis, microglia are the most abundant immune cell type within the central nervous system. Different microglia subsets in different brain areas maintain brain function and integrity.
During virus-induced encephalitis, microglia are essential for antiviral defence and protection of the brain.
Microglia activation and antiviral defence are regulated by crosstalk between neurons, astrocytes, and other cell types in the brain.
Microglia activation may have detrimental effects by causing direct or indirect loss of neurons and disturbance of tissue integrity, eventually causing long-term sequelae.
Innovative methodologies are being used to study microglial function in experimental and clinical settings to refine concepts about the roles of microglia in viral encephalitis.
Improved understanding of microglial function in the virus-infected brain is essential for the development of novel treatments for viral encephalitis.
Microglia are resident immune cells of the central nervous system (CNS) with multiple functions in health and disease. Their response during encephalitis depends on whether inflammation is triggered in a sterile or infectious manner, and in the latter case on the type of the infecting pathogen. Even though recent technological innovations advanced the understanding of the broad spectrum of microglia responses during viral encephalitis (VE), it is not entirely clear which microglia gene expression profiles are associated with antiviral and detrimental activities. Here, we review novel approaches to study microglia and the latest concepts of their function in VE. Improved understanding of microglial functions will be essential for the development of new therapeutic interventions for VE.
Access this article: https://doi.org/10.1016/j.tins.2021.11.004
Title: Immune gene network of neurological diseases: Multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD)
Authors: Shradha Mukherjee
Type: Research Article of Trends in Neurosciences
Neurological diseases, such as MS, AD, PD and HD, are a major health concern of the elderly population, but still therapeutic options are limited. Recent advances in genomic sequencing and bioinformatics, present an opportunity to understand mechanisms of these diseases for identification of therapeutic targets. Several studies have shown association of immune dysfunction with immune system mediated neurological disease, MS, as well as neurodegenerative diseases (AD, PD and HD). However, similarities and differences in role of the immune system, immune pathways and immune cell types in these diseases remains unknown. In this study, immune cell type signature genes in gene networks associated with neurological diseases, MS, AD, PD and HD was investigated using meta-analysis and bioinformatics methods. Application of Weighted Gene Co-expression Network Analysis (WGCNA) on publicly available gene expression datasets (microarray and RNA-seq) revealed a ModArray_04 module (microarray) or ModRNAseq_06 module (RNA-seq), significantly associated with MS, AD, PD and HD. Hypergeometric enrichment test revealed significant enrichment of immune cell type genes in these neurological disease modules. This study demonstrates that immune system mediated neurological disease, MS and neurodegenerative diseases (AD, PD and HD), share a common gene network characterized by immune cell type signature genes (microglia, monocytes and macrophages) and are probable targets for therapeutic intervention. In summary, this work shows a connection between MS, a disease where the role of the immune system and inflammation is established, and neurodegenerative diseases (AD, PD and HD) where the role of inflammation is still a hypothesis.
Access this article: https://doi.org/10.1016/j.heliyon.2021.e08518
Title: Gene-environment-gut interactions in Huntington’s disease mice are associated with environmental modulation of the gut microbiome
Authors: Carolina Gubert, Chloe Jane Love, Saritha Kodikara, Jamie Jie Mei Liew, Thibault Renoir, Kim-Anh Lê Cao, Anthony John Hannan
Type: Article of Trends in Neurosciences
Gastrointestinal structure and motility are intact at an early stage in a HD mouse model.
There is sexual dimorphism in the presentation of the HD gut dysbiosis phenotype.
Bacteroidales, Lachnospirales and Oscillospirales bacteria are affected by experience.
Environmental enrichment and exercise may modulate HD via the microbiota-gut-brain axis.
Gut dysbiosis in Huntington’s disease (HD) has recently been reported using microbiome profiling in R6/1 HD mice and replicated in clinical HD. In HD mice, environmental enrichment (EE) and exercise (EX) were shown to have therapeutic impacts on the brain and associated symptoms. We hypothesize that these housing interventions modulate the gut microbiome, configuring one of the mechanisms that mediate their therapeutic effects observed in HD. We exposed R6/1 mice to a protocol of either EE or EX, relative to standard-housed control conditions, before the onset of gut dysbiosis and motor deficits. We characterized gut structure and function, as well as gut microbiome profiling using 16S rRNA sequencing. Multivariate analysis identified the orders Bacteroidales, Lachnospirales and Oscillospirales as the main bacterial signatures that discriminate the housing conditions. Our findings suggest a promising role for the gut microbiome in mediating the effects of extended EE and EX exposure in HD mice.
Access this article: https://doi.org/10.1016/j.isci.2021.103687
Title: The many dimensions of human hippocampal organization and (dys)function
Authors: Sarah Genon, Boris C. Bernhardt, Renaud La Joie, Katrin Amunts, Simon B. Eickhoff
Type: Review of Trends in Neurosciences
Magnetic resonance imaging–based parcellation of the hippocampal formation and gradient mapping are data-driven techniques that can capture many dimensions of hippocampal organization and provide readily usable outcomes.
Features of cortical architecture, such as local connectivity and microstructure, reveal differentiation within the hippocampal formation along the medial–lateral axis. This organizational dimension seemingly reflects local information-processing organization.
Neuroimaging markers tapping into hippocampal integration into large-scale networks (i.e., whole-brain connectivity) highlight the long-axis differentiation.
The long-axis organization corresponds to a molecular gradient and differential integration across distinct behavioral systems.
Capitalizing on gradients and parcellations maps, the long-axis organization of the hippocampal formation can be related to behavioral phenotypes in healthy and clinical populations.
The internal organization of hippocampal formation has been studied for more than a century. Although early accounts emphasized its subfields along the medial–lateral axis, findings in recent decades have highlighted also the anterior-to-posterior (i.e., longitudinal) axis as a key contributor to this brain region’s functional organization. Hence, understanding of hippocampal function likely demands characterizing both medial-to-lateral and anterior-to-posterior axes, an approach that has been concretized by recent advances in in vivo parcellation and gradient mapping techniques. Following a short historical overview, we review the evidence provided by these approaches in brain-mapping studies, as well as the perspectives they open for addressing the behavioral relevance of the interacting organizational axes in healthy and clinical populations.
Access this article: https://doi.org/10.1016/j.tins.2021.10.003
Title: Proteostatic regulation in neuronal compartments
Authors: Stefano L. Giandomenico, Beatriz Alvarez-Castelao, Erin M. Schuman
Type: Review of Trends in Neurosciences
Dynamic local regulation of protein synthesis and degradation allows neuronal synapses to modify their proteome autonomously during plasticity.
While our understanding of how mRNAs are localized to different neuronal compartments has rapidly advanced, a comprehensive and mechanistic understanding of how synaptic activity triggers translation of certain transcripts over others is still lacking.
The UPS degrades protein substrates selectively and specifically, but the local role of the UPS in neuronal compartments remains underexplored. Recent efforts in chemical biology and proteomics have established new promising tools and techniques to bridge this knowledge gap.
PTMs are a rich regulatory resource in cells. Future efforts should focus on broadening our knowledge of local regulation of PTMs in response to neuronal activity and how specific PTMs contribute to neuronal proteostasis.
Neurons continuously adapt to external cues and challenges, including stimulation, plasticity-inducing signals and aging. These adaptations are critical for neuronal physiology and extended survival. Proteostasis is the process by which cells adjust their protein content to achieve the specific protein repertoire necessary for cellular function. Due to their complex morphology and polarized nature, neurons possess unique proteostatic requirements. Proteostatic control in axons and dendrites must be implemented through regulation of protein synthesis and degradation in a decentralized fashion, but at the same time, it requires integration, at least in part, in the soma. Here, we discuss current understanding of neuronal proteostasis, as well as open questions and future directions requiring further exploration.
Access this article: https://doi.org/10.1016/j.tins.2021.08.002