Autism spectrum disorder (ASD) and dyslexia are both neurodevelopmental disorders with high prevalence in children. Both disorders have strong genetic basis, and share similar social communication deficits co-occurring with impairments of reading or language. However, whether these two disorders share common genetic risks remain elusive. DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia. Dock4 is important for neuronal development and social behaviors. Two DOCK4 variations, Exon27-52 deletion (protein product: Dock4-945VS) and a missense mutation at rs2074130 (protein product: Dock4-R853H), are associated with dyslexia and/or ASD with reading difficulties. The present study explores the molecular and cellular functions of these two DOCK4 variants on neuronal development, by comparing them with the wild-type Dock4 protein. Notably, it is revealed that both mutants of Dock4 showed decreased ability to activate not only Rac1, but also another small GTPase Rap1. Consistently, both mutants were dysfunctional for regulation of cell morphology and cytoskeleton. Using Neuro-2a cells and hippocampus neurons as models, we found that both mutants had compromised function in promoting neurite outgrowth and dendritic spine formation. Electrophysiological recordings further showed that R853H partially lost the ability to promote excitatory synaptic transmission, whereas 945VS totally lost the ability. Together, we identified R853 as a previously uncharacterized site for the regulation of the integrity of Dock4 function, and provides insights in understanding the common molecular pathophysiology of ASD and dyslexia.
Abstract Natural killer (NK) cells are essential components of the innate lymphoid cell family that work as both cytotoxic effectors and immune regulators. Accumulating evidence points to interactions between NK cells and the central nervous system (CNS). Here, we review the basic knowledge of NK cell biology and recent advances in their roles in the healthy CNS and pathological conditions, with a focus on normal aging, CNS autoimmune diseases, neurodegenerative diseases, cerebrovascular diseases, and CNS infections. We highlight the crosstalk between NK cells and diverse cell types in the CNS and the potential value of NK cells as novel therapeutic targets for CNS diseases.
Abstract Background Alzheimer’s disease (AD) is a progressive neurodegenerative disease and apolipoprotein E (APOE) genotypes (APOE2, APOE3, and APOE4) show different AD susceptibility. Previous studies indicated that individuals carrying the APOE2 allele reduce the risk of developing AD, which may be attributed to the potential neuroprotective role of APOE2. However, the mechanisms underlying the protective effects of APOE2 is still unclear. Methods We analyzed single-nucleus RNA sequencing and bulk RNA sequencing data of APOE2 and APOE3 carriers from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort. We validated the findings in SH-SY5Y cells and AD model mice by evaluating mitochondrial functions and cognitive behaviors respectively. Results The pathway analysis of six major cell types revealed a strong association between APOE2 and cellular stress and energy metabolism, particularly in excitatory and inhibitory neurons, which was found to be more pronounced in the presence of beta-amyloid (Aβ). Moreover, APOE2 overexpression alleviates Aβ1-42-induced mitochondrial dysfunction and reduces the generation of reactive oxygen species in SH-SY5Y cells. These protective effects may be due to ApoE2 interacting with estrogen-related receptor alpha (ERRα). ERRα overexpression by plasmids or activation by agonist was also found to show similar mitochondrial protective effects in Aβ1-42-stimulated SH-SY5Y cells. Additionally, ERRα agonist treatment improve the cognitive performance of Aβ injected mice in both Y maze and novel object recognition tests. ERRα agonist treatment increased PSD95 expression in the cortex of agonist-treated-AD mice. Conclusions APOE2 appears to enhance neural mitochondrial function via the activation of ERRα signaling, which may be the protective effect of APOE2 to treat AD.
Genetic studies of autism spectrum disorder (ASD) have revealed multigene variations that converge on synaptic dysfunction. DOCK4, a gene at 7q31.1 that encodes the Rac1 guanine nucleotide exchange factor Dock4, has been identified as a risk gene for ASD and other neuropsychiatric disorders. However, whether and how Dock4 disruption leads to ASD features through a synaptic mechanism remain unexplored. We generated and characterized a line of Dock4 knockout (KO) mice, which intriguingly displayed a series of ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, and perturbed object and spatial learning. Mice with conditional deletion of Dock4 in hippocampal CA1 recapitulated social preference deficit in KO mice. Examination in CA1 pyramidal neurons revealed that excitatory synaptic transmission was drastically attenuated in KO mice, accompanied by decreased spine density and synaptic content of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)- and NMDA (N-methyl-D-aspartate)-type glutamate receptors. Moreover, Dock4 deficiency markedly reduced Rac1 activity in the hippocampus, which resulted in downregulation of global protein synthesis and diminished expression of AMPA and NMDA receptor subunits. Notably, Rac1 replenishment in the hippocampal CA1 of Dock4 KO mice restored excitatory synaptic transmission and corrected impaired social deficits in these mice, and pharmacological activation of NMDA receptors also restored social novelty preference in Dock4 KO mice. Together, our findings uncover a previously unrecognized Dock4-Rac1-dependent mechanism involved in regulating hippocampal excitatory synaptic transmission and social behavior.
Impaired differentiation of newborn neurons or abnormalities at the synapses resulted from stress maladaptation could be the key etiology of depression. Recent studies have shown that mTOR, a crucial factor for neuronal differentiation and synapse development, acts as a common factor that mediates the rapid antidepression effects of several new-class antidepressants. In this study, the antidepressant-like activity of securinine, an alkaloid that has central nervous system stimulation ability, was investigated. Both securinine and its enantiomer virosecurinine exhibited potent in vitro activity on neuronal differentiation and synapse development in Neuro-2a cells and cultured hippocampal neurons, and this activity was dependent on the activation of the AKT-mTOR-S6K pathway. Interestingly, only securinine but not virosecurinine showed mTOR stimulation and antidepressant-like activity in mice. Importantly, a single dose of securinine was capable of alleviating the behavioral deficits induced by both acute and chronic stress models within 30 min of administration, suggesting that securinine has rapid onset of action. Moreover, neither a single dose nor a 3 week treatment of securinine had adverse effects on exploratory locomotion of mice. Together, this study identifies that securinine is a potent agent in promoting neuronal differentiation and synapse formation and shows rapid antidepressant-like activity, without inducing abnormal locomotion, via mTOR activation.
Tuberculous meningitis (TBM) is the most severe complication of tuberculosis (TB) and is associated with high rates of disability and mortality. Mycobacterium tuberculosis (M. tb), the infectious agent of TB, disseminates from the respiratory epithelium, breaks through the blood-brain barrier, and establishes a primary infection in the meninges. Microglia are the core of the immune network in the central nervous system (CNS) and interact with glial cells and neurons to fight against harmful pathogens and maintain homeostasis in the brain through pleiotropic functions. However, M. tb directly infects microglia and resides in them as the primary host for bacillus infections. Largely, microglial activation slows disease progression. The non-productive inflammatory response that initiates the secretion of pro-inflammatory cytokines and chemokines may be neurotoxic and aggravate tissue injuries based on damages caused by M. tb. Host-directed therapy (HDT) is an emerging strategy for modulating host immune responses against diverse diseases. Recent studies have shown that HDT can control neuroinflammation in TBM and act as an adjunct therapy to antibiotic treatment. In this review, we discuss the diverse roles of microglia in TBM and potential host-directed TB therapies that target microglia to treat TBM. We also discuss the limitations of applying each HDT and suggest a course of action for the near future.
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