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Cells Feb 2023Emerging evidence from genomics, post-mortem, and preclinical studies point to a potential dysregulation of molecular signaling at postsynaptic density (PSD) in... (Review)
Review
Dysregulated Signaling at Postsynaptic Density: A Systematic Review and Translational Appraisal for the Pathophysiology, Clinics, and Antipsychotics' Treatment of Schizophrenia.
Emerging evidence from genomics, post-mortem, and preclinical studies point to a potential dysregulation of molecular signaling at postsynaptic density (PSD) in schizophrenia pathophysiology. The PSD that identifies the archetypal asymmetric synapse is a structure of approximately 300 nm in diameter, localized behind the neuronal membrane in the glutamatergic synapse, and constituted by more than 1000 proteins, including receptors, adaptors, kinases, and scaffold proteins. Furthermore, using FASS (fluorescence-activated synaptosome sorting) techniques, glutamatergic synaptosomes were isolated at around 70 nm, where the receptors anchored to the PSD proteins can diffuse laterally along the PSD and were stabilized by scaffold proteins in nanodomains of 50-80 nm at a distance of 20-40 nm creating "nanocolumns" within the synaptic button. In this context, PSD was envisioned as a multimodal hub integrating multiple signaling-related intracellular functions. Dysfunctions of glutamate signaling have been postulated in schizophrenia, starting from the glutamate receptor's interaction with scaffolding proteins involved in the N-methyl-D-aspartate receptor (NMDAR). Despite the emerging role of PSD proteins in behavioral disorders, there is currently no systematic review that integrates preclinical and clinical findings addressing dysregulated PSD signaling and translational implications for antipsychotic treatment in the aberrant postsynaptic function context. Here we reviewed a critical appraisal of the role of dysregulated PSD proteins signaling in the pathophysiology of schizophrenia, discussing how antipsychotics may affect PSD structures and synaptic plasticity in brain regions relevant to psychosis.
Topics: Humans; Antipsychotic Agents; Schizophrenia; Post-Synaptic Density; Psychotic Disorders; Receptors, N-Methyl-D-Aspartate
PubMed: 36831241
DOI: 10.3390/cells12040574 -
Therapeutics and Clinical Risk... 2022Myasthenia gravis (MG) is a rare autoimmune disorder caused by specific autoantibodies at the neuromuscular junction. MG is classified by the antigen specificity of... (Review)
Review
Myasthenia gravis (MG) is a rare autoimmune disorder caused by specific autoantibodies at the neuromuscular junction. MG is classified by the antigen specificity of these antibodies. Acetylcholine receptor (AChR) antibodies are the most common type (74-88%), followed by anti-muscle specific kinase (MuSK) and other antibodies. While all these antibodies lead to neuromuscular transmission failure, the immuno-pathogenic mechanisms are distinct. Complement activation is a primary driver of AChR antibody-positive MG (AChR+ MG) pathogenesis. This leads to the formation of the membrane attack complex and destruction of AChR receptors and the postsynaptic membrane resulting in impaired neurotransmission and muscle weakness characteristic of MG. Broad-based immune-suppressants like corticosteroids are effective in controlling MG; however, their long-term use can be associated with significant adverse effects. Advances in translational research have led to the development of more directed therapeutic agents that are likely to alter the future of MG treatment. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of complement protein C5 and is approved for use in generalized MG. In this review, we discuss the pathophysiology of MG; the therapeutic efficacy and tolerability of eculizumab, as well as the practical guidelines for its use in MG; future studies exploring the role of eculizumab in different stages and subtypes of MG subtypes; the optimal duration of therapy and its discontinuation; the characterization of non-responder patients; and the use of biomarkers for monitoring therapy are highlighted. Based on the pathophysiologic mechanisms, emerging therapies and new therapeutic targets are also reviewed.
PubMed: 35855752
DOI: 10.2147/TCRM.S266031 -
A systematic review of common genetic variation and biological pathways in autism spectrum disorder.BMC Neuroscience Oct 2021Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by persistent deficits in social communication and interaction. Common genetic...
BACKGROUND
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by persistent deficits in social communication and interaction. Common genetic variation appears to play a key role in the development of this condition. In this systematic review, we describe the relationship between genetic variations and autism. We created a gene dataset of the genes involved in the pathogenesis of autism and performed an over-representation analysis to evaluate the biological functions and molecular pathways that may explain the associations between these variants and the development of ASD.
RESULTS
177 studies and a gene set composed of 139 were included in this qualitative systematic review. Enriched pathways in the over-representation analysis using the KEGG pathway database were mostly associated with neurotransmitter receptors and their subunits. Major over-represented biological processes were social behavior, vocalization behavior, learning and memory. The enriched cellular component of the proteins encoded by the genes identified in this systematic review were the postsynaptic membrane and the cell junction.
CONCLUSIONS
Among the biological processes that were examined, genes involved in synaptic integrity, neurotransmitter metabolism, and cell adhesion molecules were significantly involved in the development of autism.
Topics: Autism Spectrum Disorder; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Humans; Learning; Polymorphism, Genetic
PubMed: 34627165
DOI: 10.1186/s12868-021-00662-z -
Frontiers in Immunology 2021Myasthenia gravis (MG) is an autoimmune disease primarily mediated by acetylcholine receptor antibodies (AChR-Ab), cellular immune dependence, and complement system... (Review)
Review
Myasthenia gravis (MG) is an autoimmune disease primarily mediated by acetylcholine receptor antibodies (AChR-Ab), cellular immune dependence, and complement system involvement. Since the AChR on the postsynaptic membrane is destroyed by an immune attack, sufficient endplate potential cannot be generated, resulting in the development of a synaptic transmission disorder at the neuromuscular junction and in muscle weakness. The role of the complement system in MG has been demonstrated in animal models and clinical tests, and it has been determined that complement inhibition in patients with MG can prevent disease induction and reverse its progression. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of complement protein C5 and prevents autoimmune damage; additionally, it has received subsequent approval by the Federal Drug Administration of the United States for MG treatment. However, various concerns regarding the use of eculizumab persist. In this review, we have discussed the treatment time, cost effectiveness, long-term efficacy, and tolerability of eculizumab for MG treatment. We have also summarized historical information and have presented perspectives on this new therapeutic modality.
Topics: Animals; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Combined Modality Therapy; Complement Inactivating Agents; Complement System Proteins; Disease Management; Disease Susceptibility; Drug Development; Humans; Myasthenia Gravis; Treatment Outcome
PubMed: 34456922
DOI: 10.3389/fimmu.2021.715036 -
The Journal of International Advanced... Dec 2020To establish outcomes following cochlear implantation (CI) in patients with postsynaptic auditory neuropathy (AN). Systematic review and narrative synthesis. Databases...
To establish outcomes following cochlear implantation (CI) in patients with postsynaptic auditory neuropathy (AN). Systematic review and narrative synthesis. Databases searched: MEDLINE, PubMed, EMBASE, Web of Science, Cochrane Collection and ClinicalTrials.gov. No limits placed on language or year of publication. Review conducted in accordance with the PRISMA statement. Searches identified 98 studies in total, of which 14 met the inclusion criteria reporting outcomes in 25 patients with at least 28 CIs. Of these, 4 studies focused on Charcot-Marie-Tooth disease (CMT), 3 on Brown-Vialetto-Van-Laere syndrome (BVVL), 2 on Friedreich Ataxia (FRDA), 2 on Syndromic dominant optic atrophy (DOA+), 2 on Cerebellar ataxia - areflexia - pes cavus - optic atrophy - sensorineural hearing loss (CAPOS) syndrome, and 1 on Deafness-dystonia-optic neuronopathy (DDON) syndrome. All studies were Oxford Centre for Evidence Based Medicine (OCEBM) grade IV. Overall trend was towards good post-CI outcomes with 22 of the total 25 patients displaying modest to significant benefit. Hearing outcomes following CI in postsynaptic ANs are variable but generally good with patients showing improvements in hearing thresholds and speech perception. In the future, development of a clearer stratification system into pre, post, and central AN would have clinical and academic benefits. Further research is required to understand AN pathophysiology and develop better diagnostic tools for more accurate identification of lesion sites. Multicenter longitudinal studies with standardized comprehensive outcome measures including health-related quality of life data will be key in establishing a better understanding of short and long-term post-CI outcomes.
Topics: Adolescent; Adult; Child; Child, Preschool; Cochlear Implantation; Cochlear Implants; Female; Hearing Loss, Central; Hearing Loss, Sensorineural; Humans; Male; Membrane Transport Proteins; Multicenter Studies as Topic; Quality of Life; Retrospective Studies; Sodium-Potassium-Exchanging ATPase; Speech Perception
PubMed: 33136025
DOI: 10.5152/iao.2020.9035