Frontiers in Molecular Neuroscience最新文献

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder whose exact pathophysiology has not been fully understood yet. Numerous studies have suggested disruptions in the cellular architecture and neuronal activity within brain structures of individuals with ADHD, accompanied by imbalances in the immune system, oxidative stress, and metabolism.

Methods: This study aims to assess two functionally and histologically distinct brain areas involved in motor control and coordination: the motor cortex (MC) and prefrontal cortex (PFC). Namely, the morphometric analysis of the MC throughout the developmental stages of Spontaneously Hypertensive Rats (SHRs) and Wistar Kyoto Rats (WKYs). Additionally, the study aimed to investigate the levels and activities of specific immune, oxidative stress, and metabolic markers in the PFC of juvenile and maturing SHRs in comparison to WKYs.

Results: The most significant MC volume reductions occurred in juvenile SHRs, accompanied by alterations in neuronal density in these brain areas compared to WKYs. Furthermore, juvenile SHRs exhibit heightened levels and activity of various markers, including interleukin-1α (IL-1α), IL-6, serine/threonine-protein mammalian target of rapamycin, RAC-alpha serine/threonine-protein kinase, glucocorticoid receptor β, malondialdehyde, sulfhydryl groups, superoxide dismutase, peroxidase, glutathione reductase, glutathione S-transferase, glucose, fructosamine, iron, lactic acid, alanine, aspartate transaminase, and lactate dehydrogenase.

Discussion: Significant changes in the MC morphometry and elevated levels of inflammatory, oxidative, and metabolic markers in PFC might be associated with disrupted brain development and maturation in ADHD.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations or deletions in the survival motoneuron 1 (SMN1) gene, resulting in deficiency of the SMN protein that is essential for motoneuron function. Smn depletion in mice disturbs axonal RNA transport and translation, thereby contributing to axon growth impairment, muscle denervation, and motoneuron degeneration. However, the mechanisms whereby Smn loss causes axonal defects remain unclear. RNA localization and translation in axons are controlled by RNA-binding proteins (RBP) and we recently observed that the neuronal RBP Ptbp2 modulates axon growth in motoneurons. Here, we identify Smn as an interactor of Ptbp2 in the cytosolic compartments of motoneurons. We show that the expression level of Ptbp2 is reduced in axons but not in the somata of Smn-depleted motoneurons. This is accompanied by reduced synthesis of the RBP hnRNP R in axons. Re-expression of Ptbp2 in axons compensates for the deficiency of Smn and rescues the defects in axon elongation and growth cone maturation observed in Smn-deficient motoneurons. Our data suggest that Ptbp2 and Smn are components of cytosolic mRNP particles, contributing to the precise spatial and temporal control of protein synthesis within axons and axon terminals.

Background: Head and neck paragangliomas (HNPGLs) are rare neuroendocrine tumors that pose significant challenges in both diagnosis and treatment. The pathogenic mechanism remains unclear, and there is no proteomic analysis-based molecular classification. Therefore, gaining a deeper understanding of this disease from the protein level is crucial because proteins play a fundamental role in the occurrence and development of tumors.

Methods: We collected 44 tumor samples from patients diagnosed with HNPGL. The adrenal paraganglioma tissue (N = 46) was used as the disease control group and the chorda tympani nerves (N = 18) were used as the control group. High-pH reversed-phase liquid chromatography and liquid chromatography with tandem mass spectrometry analyses were used to build an integrated protein database of tumor samples. We then obtained two sets of differentially expressed proteins between the tumor group and the control group to identify the unique proteomic signatures of HNPGLs. Ingenuity pathway analysis annotations were used to perform the functional analysis. Subsequently, we developed a clinically relevant molecular classification for HNPGLs that connected the clinical characteristics with meaningful proteins and pathways to explain the varied clinical manifestations.

Results: We identified 6,640 proteins in the HNPGL group, and 314 differentially expressed proteins unique to HNPGL were discovered via inter-group comparison. We identified two HNPGL subgroups that significantly differed in clinical manifestation and proteomic characteristics. On the basis of the proteomic results, we proposed a pathogenic mechanism underlying HNPGL.

Conclusion: We conducted a comprehensive analysis of the molecular mechanisms of HNPGL to build, for the first time, a clinically relevant molecular classification. By focusing on differential proteomic analyses between different types of paragangliomas, we were able to obtain a comprehensive description of the proteomic characteristics of HNPGL, which will be valuable for the search for significant biomarkers as a new treatment method for HNPGL.

Background: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by increased inflammation and immune responses, oxidative injury, mitochondrial dysfunction, and iron dyshomeostasis leading to demyelination and axonal damage. In MS, incomplete remyelination results in chronically demyelinated axons and degeneration coinciding with disability. This suggests a failure in the ability to remyelinate in MS, however, the precise underlying mechanisms remain unclear. We aimed to identify proteins whose expression was altered in chronic inactive white matter lesions and periplaque white matter in MS tissue to reveal potential pathophysiological mechanisms.

Methods: Laser capture microdissection coupled to proteomics was used to interrogate spatially altered changes in formalin-fixed paraffin-embedded brain tissue from three chronic MS individuals and three controls with no apparent neurological complications. Histopathological maps guided the capture of inactive lesions, periplaque white matter, and cortex from chronic MS individuals along with corresponding white matter and cortex from control tissue. Label free quantitation by liquid chromatography tandem mass spectrometry was used to discover differentially expressed proteins between the various brain regions.

Results: In addition to confirming loss of several myelin-associated proteins known to be affected in MS, proteomics analysis of chronic inactive MS lesions revealed alterations in myelin assembly, metabolism, and cytoskeletal organization. The top altered proteins in MS inactive lesions compared to control white matter consisted of PPP1R14A, ERMN, SIRT2, CARNS1, and MBLAC2.

Conclusion: Our findings highlight proteome changes in chronic inactive MS white matter lesions and periplaque white matter, which may be crucial for proper myelinogenesis, bioenergetics, focal adhesions, and cellular function. This study highlights the importance and feasibility of spatial approaches such as laser capture microdissection-based proteomics analysis of pathologically distinct regions of MS brain tissue. Identification of spatially resolved changes in the proteome of MS brain tissue should aid in the understanding of pathophysiological mechanisms and the development of novel therapies.