p62/sequestosome-1 as a severity-reflecting plasma biomarker in Charcot-Marie-Tooth disease type 1A.

Autophagy is a self-degradation system for recycling to maintain homeostasis. p62/sequestosome-1 (p62) is an autophagy receptor that accumulates in neuroglia in neurodegenerative diseases. The objective of this study was to determine the elevation of plasma p62 protein levels in patients with Charcot-Marie-Tooth disease 1A (CMT1A) for its clinical usefulness to assess disease severity.

Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models.

Promotion of mitophagy is considered a promising strategy for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). The development of mitophagy-specific inducers with low toxicity and defined molecular mechanisms is essential for the clinical application of mitophagy-based therapy. The aim of this study was to investigate the potential of a novel small-molecule mitophagy inducer, ALT001, as a treatment for AD.

Targeting SARM1 improves autophagic stress-induced axonal neuropathy.

AAV: adeno-associated virus; ATF3: activating transcription factor 3; ATG7: autophagy related 7; AVIL: advillin; cADPR: cyclic ADP ribose; CALC: calcitonin/calcitonin-related polypeptide; CMT: Charcot-Marie-Tooth disease; cKO: conditional knockout; DEG: differentially expressed gene; DRG: dorsal root ganglion; FE-SEM: field emission scanning electron microscopy; IF: immunofluorescence; NCV: nerve conduction velocity; PVALB: parvalbumin; RAG: regeneration-associated gene; ROS: reactive oxygen species; SARM1: sterile alpha and HEAT/Armadillo motif containing 1; : synapsin I.

Neural cell adhesion molecule 1 is a cellular target engaged plasma biomarker in demyelinating Charcot-Marie-Tooth disease.

Background And Purpose: Elevated plasma concentrations of neural cell adhesion molecule 1 (NCAM1) and p75 neurotrophin receptor (p75) in patients with peripheral neuropathy have been reported. This study aimed to determine the specificity of plasma concentration elevation of either NCAM1 or p75 in a subtype of Charcot-Marie-Tooth disease (CMT) and its correlation with pathologic nerve status and disease severity.

Methods: Blood samples were collected from 138 patients with inherited peripheral neuropathy and 51 healthy controls.

Regulation of the V-ATPase subunit ATP6V0D2 and its role in demyelination after peripheral nerve injury.

After peripheral nerve injury, demyelinating Schwann cells discharge myelin debris and macrophages execute myelin degradation, leading to demyelination of degenerating axons, which is essential for efficient nerve regeneration. In this study, we show that vacuolar-type proton ATPase subunit d2 (Atp6v0d2) is among the most highly upregulated genes in degenerating mouse sciatic nerves after nerve injury using microarray analysis. ATP6V0D2 is mostly expressed in macrophages of injured nerves.

COUP-TFII plays a role in cAMP-induced Schwann cell differentiation and in vitro myelination by up-regulating Krox20.

Schwann cells (SCs) are known to produce myelin for saltatory nerve conduction in the peripheral nervous system (PNS). Schwann cell differentiation and myelination processes are controlled by several transcription factors including Sox10, Oct6/Pou3f1, and Krox20/Egr2. Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII/NR2F2) is an orphan receptor that plays a role in the development and differentiation.

Trichinella Infection Ameliorated Vincristine-Induced Neuroinflammation in Mice.

Vincristine (VCR) is a chemotherapeutic agent widely used in treatment of malignancies. However, VCR has a limitation in use since it commonly causes a painful neuropathy (VCR-induced peripheral neuropathy, VIPN). Inflammatory cytokines secreted by immune cells such as macrophages can exacerbate allodynia and hyperalgesia, because inhibiting the inflammatory response is a treatment target for VIPN.

Involvement of the miR-363-5p/P2RX4 Axis in Regulating Schwann Cell Phenotype after Nerve Injury.

Although microRNAs (miRNAs or miRs) have been studied in the peripheral nervous system, their function in Schwann cells remains elusive. In this study, we performed a microRNA array analysis of cyclic adenosine monophosphate (cAMP)-induced differentiated primary Schwann cells. pathway enrichment analysis of the target genes showed that upregulated miRNAs (mR212-5p, miR335, miR20b-5p, miR146b-3p, and miR363-5p) were related to the calcium signaling pathway, regulation of actin cytoskeleton, retrograde endocannabinoid signaling, and central carbon metabolism in cancer.

Scaffolding protein Gab2 is involved in postnatal development and lipopolysaccharide-induced activation of microglia in the mouse brain.

Grb2-associated-binding protein-2 (Gab2) is a member of the Gab/DOS family and functions as an adapter protein downstream of several growth factor signaling pathways. Gab2 is considered an Alzheimer's disease susceptibility gene. However, the role of Gab2 in the brain is still largely unknown.

Potential neuron-autonomous Purkinje cell degeneration by 2',3'-cyclic nucleotide 3'-phosphodiesterase promoter/Cre-mediated autophagy impairments.

Studies of neuroglial interaction largely depend on cell-specific gene knockout (KO) experiments using Cre recombinase. However, genes known as glial-specific genes have recently been reported to be expressed in neuroglial stem cells, leading to the possibility that a glia-specific Cre driver results in unwanted gene deletion in neurons, which may affect sound interpretation. 2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNP) is generally considered to be an oligodendrocyte (OL) marker.

Finger drop sign as a new variant of acute motor axonal neuropathy.

We propose the finger drop sign as a new clinical variant of acute motor axonal neuropathy (AMAN) defined by immunological and radiological evidence. We identified eight consecutive patients who had AMAN. All of them developed prominent involvement of the finger extensors.

Exosomes derived from differentiated Schwann cells inhibit Schwann cell migration via microRNAs.

Exosomes derived from Schwann cells have been known to have a variety of functions in the development and repair of the peripheral nervous system, and cyclic AMP (cAMP) is a key inducer of Schwann cell differentiation. In the present study, we aimed to study the effect of exosomes derived from differentiated Schwann cells on the expression of microRNAs (miRNAs). To show that miRNAs were altered from exosomes derived from Schwann cells, we conducted next-generation sequencing (NGS) arrays with exosomes derived from cAMP-induced differentiated Schwann cells and control.

Loss-of-function of EBP50 is a new cause of hereditary peripheral neuropathy: EBP50 functions in peripheral nerve system.

Finding causative genetic mutations is important in the diagnosis and treatment of hereditary peripheral neuropathies. This study was conducted to find new genes involved in the pathophysiology of hereditary peripheral neuropathy. We identified a new mutation in the EBP50 gene, which is co-segregated with neuropathic phenotypes, including motor and sensory deficit in a family with Charcot-Marie-Tooth disease.

Behind the pathology of macrophage-associated demyelination in inflammatory neuropathies: demyelinating Schwann cells.

In inflammatory peripheral demyelinating disorders, demyelination represents segmental demyelination in which the myelin sheath of a myelinating Schwann cell (SC) is completely removed by macrophages or a partial myelin degeneration in the paranode occurring due to autoantibodies attacking the node/paranode. For the segmental demyelination from living myelin-forming SCs, macrophages infiltrate within the endoneurium and insinuate between myelin lamellae and the cytoplasm of SCs, and the myelin is then removed via phagocytosis. During the macrophage invasion into the SC cytoplasm from the node of Ranvier and internodal areas, the attacked SCs do not remain quiescent but transdifferentiate into inflammatory demyelinating SCs (iDSCs), which exhibit unique demyelination pathologies, such as myelin uncompaction from Schmidt-Lanterman incisures with myelin lamellae degeneration.

Differential expression of circular RNAs in the proximal and distal segments of the sciatic nerve after injury.

To investigate the functions of circular RNAs (circRNAs) in axonal regeneration and degeneration after injury, circRNA expression profiles in the injured peripheral nerves were determined using a circRNA-based microarray. The results showed that 281 upregulated and 261 downregulated circRNAs were found in the proximal stump of the sciatic nerve after injury. In the distal stump after injury, 217 circRNAs were upregulated and 224 circRNAs were downregulated.

Serum CXCL13 reflects local B-cell mediated inflammatory demyelinating peripheral neuropathy.

Immune damages on the peripheral myelin sheath under pro-inflammatory milieu result in primary demyelination in inflammatory demyelinating neuropathy. Inflammatory cytokines implicating in the pathogenesis of inflammatory demyelinating neuropathy have been used for the development of potential biomarkers for the diagnosis of the diseases. In this study, we have found that macrophages, which induce demyelination, expressed a B-cell-recruiting factor CXC chemokine ligand 13 (CXCL13) in mouse and human inflammatory demyelinating nerves.

Heat Shock Protein 90 is Required for cAMP-Induced Differentiation in Rat Primary Schwann Cells.

Schwann cells (SCs) play an important role in producing myelin for rapid neurotransmission in the peripheral nervous system. Activation of the differentiation and myelination processes in SCs requires the expression of a series of transcriptional factors including Sox10, Oct6/Pou3f1, and Egr2/Krox20. However, functional interactions among several transcription factors are poorly defined and the important components of the regulatory network are still unknown.

Downregulation MIWI-piRNA regulates the migration of Schwann cells in peripheral nerve injury.

Although MIWI (PIWI in humans) regulates spermatogenesis and translation machinery, its role in peripheral nerve injury is poorly understood. In this study, we characterized the expression profiles of MIWI after sciatic nerve injury. The results revealed that MIWI was downregulated after sciatic nerve injury.

p75 and neural cell adhesion molecule 1 can identify pathologic Schwann cells in peripheral neuropathies.

Objective: Myelinated Schwann cells (SCs) in adult peripheral nerves dedifferentiate into immature cells in demyelinating neuropathies and Wallerian degeneration. This plastic SC change is actively involved in the myelin destruction and clearance as demyelinating SCs (DSCs). In inherited demyelinating neuropathy, pathologically differentiated and dysmyelinated SCs constitute the main nerve pathology.

Pattern of Extraocular Muscle Involvements in Miller Fisher Syndrome.

Background And Purpose: The most-common initial manifestation of Miller Fisher syndrome (MFS) is diplopia due to acute ophthalmoplegia. However, few studies have focused on ocular motility findings in MFS. This study aimed to determine the pattern of extraocular muscle (EOM) paresis in MFS patients.

miR-381 Attenuates Peripheral Neuropathic Phenotype Caused by Overexpression of PMP22.

Charcot-Marie Tooth disease type 1A (CMT1A), the major type of CMT, is caused by duplication of peripheral myelin protein 22 () gene whose overexpression causes structural and functional abnormalities in myelination. We investigated whether miRNA-mediated regulation of PMP22 expression could reduce the expression level of PMP22, thereby alleviating the demyelinating neuropathic phenotype of CMT1A. We found that several miRNAs were down-regulated in C22 mouse, a CMT1A mouse model.

Assessment of mitophagy in mt-Keima revealed an essential role of the PINK1-Parkin pathway in mitophagy induction .

Mitophagy has been implicated in mitochondrial quality control and in various human diseases. However, the study of mitophagy remains limited. We previously explored mitophagy using a transgenic mouse expressing the mitochondria-targeted fluorescent protein Keima (mt-Keima).