Whole-exome sequencing identifies a novel mutation in spermine synthase gene (SMS) associated with Snyder-Robinson Syndrome.

BACKGROUND: Loss of function mutations in the spermine synthase gene (SMS) have been reported to cause a rare X-linked intellectual disability known as Snyder-Robinson Syndrome (SRS). Besides intellectual disability, SRS is also characterized by reduced bone density, osteoporosis and facial dysmorphism. SRS phenotypes evolve with age from childhood to adulthood. METHODS: Whole exome sequencing was performed to know the causative gene/pathogenic variant. Later we confirmed the pathogenic variant through Sanger sequencing. Furthermore, we also performed the mutational analysis through HOPE SERVER and SWISS-MODEL. Also, radiographs were also obtained for affected individual to confirm the disease features. RESULTS: In this article, we report the first Pakistani family consisting of three patients with SRS and a novel missense pathogenic variant in the SMS gene (c.905 C > T p.(Ser302Leu)). In addition to the typical phenotypes, one patient presented with early-onset seizures. Clinical features, genetic and in-silico analysis linked the affected patients of the family with Snyder-Robinson and suggest that this novel mutation affects the spermine synthase activity. CONCLUSION: A novel missense variant in the SMS, c.905C > T p. (Ser302Leu), causing Snyder- Robinson Syndrome (SRS) is reported in three members of Pakistani Family.

The decreased astrocyte-microglia interaction reflects the early characteristics of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease often associated with olfactory dysfunction. Aß is a typical AD hall marker, but Aß-induced molecular alterations in olfactory memory remain unclear. In this study, we used a 5xFAD mouse model to investigate Aß-induced olfactory changes. Results showed that 4-month-old 5xFAD have olfactory memory impairment accompanied by piriform cortex neuron activity decline and no sound or working memory impairment. In addition, synapse and glia functional alteration is consistent across different ages at the proteomic level. Microglia and astrocyte specific proteins showed strong interactions in the conserved co-expression network module. Moreover, this interaction declines only in mild cognitive impairment patients in human postmortem brain proteomic data. This suggests that astrocytes-microglia interaction may play a leading role in the early stage of Aß-induced olfactory memory impairment, and the decreasing of their synergy may accelerate the neurodegeneration.

Neuronal Circuits Associated with Fear Memory: Potential Therapeutic Targets for Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that is associated with long-lasting memories of traumatic experiences. Extinction and discrimination of fear memory have become therapeutic targets for PTSD. Newly developed optogenetics and advanced in vivo imaging techniques have provided unprecedented spatiotemporal tools to characterize the activity, connectivity, and functionality of specific cell types in complicated neuronal circuits. The use of such tools has offered mechanistic insights into the exquisite organization of the circuitry underlying the extinction and discrimination of fear memory. This review focuses on the acquisition of more detailed, comprehensive, and integrated neural circuits to understand how the brain regulates the extinction and discrimination of fear memory. A future challenge is to translate these researches into effective therapeutic treatment for PTSD from the perspective of precise regulation of the neural circuits associated with the extinction and discrimination of fear memories.

A potential biomarker of preclinical Alzheimer's disease: The olfactory dysfunction and its pathogenesis-based neural circuitry impairments.

The olfactory dysfunction can signal and act as a potential biomarker of preclinical AD. However, the precise regulatory mechanism of olfactory function on the neural pathogenesis of AD is still unclear. The impairment of neural networks in olfaction system has been shown to be tightly associated with AD. As key brain regions of the olfactory system, the olfactory bulb (OB) and the piriform cortex (PCx) have a profound influence on the olfactory function. Therefore, this review will explore the mechanism of olfactory dysfunction in preclinical AD in the perspective of abnormal neural networks in the OB and PCx and their associated brain regions, especially from two aspects of aberrant oscillations and synaptic plasticity damages, which help better understand the underlying mechanism of olfactory neural network damages related to AD.

The age-related microglial transformation in Alzheimer's disease pathogenesis.

Neuroinflammatory responses mediated by microglia, the resident immune cells of the central nervous system, have long been a subject of study in the field of Alzheimer's disease (AD). Microglia express a wide range of receptors that act as molecular sensors, through which they can fulfill their various functions. In this review, we first analyzed the changes in the expression levels of microglial membrane receptors SR-A, TREM2, CD36, CD33, and CR3 in aging and AD and described the different roles of these receptors in amyloid-beta clearance and inflammatory responses. Two classical hallmarks of AD are extracellular amyloid-beta deposits and intracellular aggregated phosphorylated tau. In AD, microglia reaction was initially thought to be triggered by amyloid deposits. New evidence showed it also associated with increased phosphorylation of tau. However, which first appeared and induced activated microglia is not clear. Then we summarized diverse opinions on it. Besides, as AD is tightly linked to aging, and microglia changes dramatically on aging, yet the relative impacts of both aging and microglia are less frequently considered, so at last, we discussed the roles of aging microglia in AD. We hope to provide a reference for subsequent research.