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Cold Spring Harbor Perspectives in... Apr 2017SUMMARYNeurofilaments (NFs) are unique among tissue-specific classes of intermediate filaments (IFs) in being heteropolymers composed of four subunits (NF-L... (Review)
Review
SUMMARYNeurofilaments (NFs) are unique among tissue-specific classes of intermediate filaments (IFs) in being heteropolymers composed of four subunits (NF-L [neurofilament light]; NF-M [neurofilament middle]; NF-H [neurofilament heavy]; and α-internexin or peripherin), each having different domain structures and functions. Here, we review how NFs provide structural support for the highly asymmetric geometries of neurons and, especially, for the marked radial expansion of myelinated axons crucial for effective nerve conduction velocity. NFs in axons extensively cross-bridge and interconnect with other non-IF components of the cytoskeleton, including microtubules, actin filaments, and other fibrous cytoskeletal elements, to establish a regionally specialized network that undergoes exceptionally slow local turnover and serves as a docking platform to organize other organelles and proteins. We also discuss how a small pool of oligomeric and short filamentous precursors in the slow phase of axonal transport maintains this network. A complex pattern of phosphorylation and dephosphorylation events on each subunit modulates filament assembly, turnover, and organization within the axonal cytoskeleton. Multiple factors, and especially turnover rate, determine the size of the network, which can vary substantially along the axon. NF gene mutations cause several neuroaxonal disorders characterized by disrupted subunit assembly and NF aggregation. Additional NF alterations are associated with varied neuropsychiatric disorders. New evidence that subunits of NFs exist within postsynaptic terminal boutons and influence neurotransmission suggests how NF proteins might contribute to normal synaptic function and neuropsychiatric disease states.
Topics: Animals; Biomarkers; Humans; Intermediate Filaments; Mental Disorders; Neurofilament Proteins; Organelles; Protein Processing, Post-Translational
PubMed: 28373358
DOI: 10.1101/cshperspect.a018309 -
Current Pharmaceutical Design 2020Neurofilaments: light, medium, and heavy (abbreviated as NF-L, NF-M, and NF-H, respectively), which belong to Type IV intermediate filament family (IF), are... (Review)
Review
Neurofilaments: light, medium, and heavy (abbreviated as NF-L, NF-M, and NF-H, respectively), which belong to Type IV intermediate filament family (IF), are neuron-specific cytoskeletal components. Neurofilaments are axonal structural components and integral components of synapses, which are important for neuronal electric signal transmissions along the axons and post-translational modification. Abnormal assembly of neurofilaments is found in several human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy (SMA), and hereditary sensory-motor neuropathy (HSMN). In addition, those pathological neurofilament accumulations are known in α-synuclein in Parkinson's disease (PD), Aβ and tau in Alzheimer's disease (AD), polyglutamine in CAG trinucleotide repeat disorders, superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP43), neuronal FUS proteins, optineurin (OPTN), ubiquilin 2 (UBQLN2), and dipeptide repeat protein (DRP) in amyotrophic lateral sclerosis (ALS). When axon damage occurs in central nervous disorders, neurofilament proteins are released and delivered into cerebrospinal fluid (CSF), which are then circulated into blood. New quantitative analyses and assay techniques are well-developed for the detection of neurofilament proteins, particularly NF-L and the phosphorylated NF-H (pNF-H) in CSF and serum. This review discusses the potential of using peripheral blood NF quantities and evaluating the severity of damage in the nervous system. Intermediate filaments could be promising biomarkers for evaluating disease progression in different nervous system disorders.
Topics: Biomarkers; Humans; Neurodegenerative Diseases; Neurofilament Proteins; Prognosis
PubMed: 31820696
DOI: 10.2174/1381612825666191210154535 -
Brain Research Bulletin Jan 2023Neurofilament and tau proteins are neuron-specific cytoskeletal proteins that are enriched in axons, regulated by many of the same protein kinases, interact physically,... (Review)
Review
Neurofilament and tau proteins are neuron-specific cytoskeletal proteins that are enriched in axons, regulated by many of the same protein kinases, interact physically, and are the principal constituents of neurofibrillary lesions in major adult-onset dementias. Both proteins share functions related to the modulation of stability and functions of the microtubule network in axons, axonal transport and scaffolding of organelles, long-term synaptic potentiation, and learning and memory. Expression of these proteins is regulated not only at the transcriptional level but also through posttranscriptional control of pre-mRNA splicing, mRNA stability, transport, localization, local translation and degradation. Current evidence suggests that posttranscriptional determinants of their levels are usually regulated by RNA-binding proteins and microRNAs primarily through 3'-untranslated regions of neurofilament and tau mRNAs. Dysregulations of neurofilament and tau expression caused by mutations or pathologies of RNA-binding proteins such as TDP43, FUS and microRNAs are increasingly recognized in association with varied neurological disorders. In this review, we summarize the current understanding of posttranscriptional control of neurofilament and tau by examining the posttranscriptional regulation of neurofilament and tau by RNA-binding proteins and microRNAs implicated in health and diseases.
Topics: Neurofilament Proteins; tau Proteins; Axons; Axonal Transport; MicroRNAs; RNA-Binding Proteins
PubMed: 36441047
DOI: 10.1016/j.brainresbull.2022.10.017 -
Journal of Neurology, Neurosurgery, and... Aug 2019In the management of neurological diseases, the identification and quantification of axonal damage could allow for the improvement of diagnostic accuracy and prognostic... (Review)
Review
In the management of neurological diseases, the identification and quantification of axonal damage could allow for the improvement of diagnostic accuracy and prognostic assessment. Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. Its levels increase in cerebrospinal fluid (CSF) and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including inflammatory, neurodegenerative, traumatic and cerebrovascular diseases. New immunoassays able to detect biomarkers at ultralow levels have allowed for the measurement of NfL in blood, thus making it possible to easily and repeatedly measure NfL for monitoring diseases' courses. Evidence that both CSF and blood NfL may serve as diagnostic, prognostic and monitoring biomarkers in neurological diseases is progressively increasing, and NfL is one of the most promising biomarkers to be used in clinical and research setting in the next future. Here we review the most important results on CSF and blood NfL and we discuss its potential applications and future directions.
Topics: Biomarkers; Humans; Nervous System Diseases; Neurofilament Proteins; Prognosis
PubMed: 30967444
DOI: 10.1136/jnnp-2018-320106 -
Cellular and Molecular Life Sciences :... Dec 2004The function of neurofilaments, the major component in large myelinated neurons, is not well understood even though they were discovered as structures over 100 years... (Review)
Review
The function of neurofilaments, the major component in large myelinated neurons, is not well understood even though they were discovered as structures over 100 years ago. Recent studies have suggested that neuro-filaments are closely related to many neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson disease Alzheimer disease, and diabetes. Using in vitro assays, cultures and transgenic mice, these studies provided new insights into neurofilament function. The function of each subunit, the relationship of neurofilaments with other cytoskeletal elements and their clinical significance are topics of increasing attention.
Topics: Animals; Biological Transport; Disease Models, Animal; Gene Expression Regulation; Humans; Neurodegenerative Diseases; Neurofilament Proteins; Protein Processing, Post-Translational
PubMed: 15583867
DOI: 10.1007/s00018-004-4268-8 -
Biochemistry and Cell Biology =... 1995Neurofilament proteins (NFPs) are highly phosphorylated molecules in the axonal compartment of the adult nervous system. The phosphorylation of NFP is considered an... (Review)
Review
Neurofilament proteins (NFPs) are highly phosphorylated molecules in the axonal compartment of the adult nervous system. The phosphorylation of NFP is considered an important determinant of filament caliber, plasticity, and stability. This process reflects the function of NFs during the lifetime of a neuron from differentiation in the embryo through long-term activity in the adult until aging and environmental insult leads to pathology and ultimately death. NF function is modulated by phosphorylation-dephosphorylation in each of these diverse neuronal states. In this review, we have summarized some of these properties of NFP in adult nervous tissue, mostly from work in our own laboratory. Identification of sites phosphorylated in vivo in high molecular weight NFP (NF-H) and properties of NF-associated and neural-specific kinases phosphorylating specific sites in NFP are described. A model to explain the role of NF phosphorylation in determining filament caliber, plasticity, and stability is proposed.
Topics: Amino Acid Sequence; Animals; Humans; Intermediate Filament Proteins; Molecular Sequence Data; Neurofilament Proteins; Neurons; Peptide Fragments; Phosphorylation; Protein Kinases; Protein Structure, Tertiary
PubMed: 8714676
DOI: 10.1139/o95-063 -
Cytoskeleton (Hoboken, N.J.) Jul 2019Charcot-Marie-Tooth disease Type 2E/1F (CMT2E/1F) is a peripheral neuropathy caused by mutations in neurofilament protein L (NFL), which is one of five neurofilament...
Charcot-Marie-Tooth disease Type 2E/1F (CMT2E/1F) is a peripheral neuropathy caused by mutations in neurofilament protein L (NFL), which is one of five neurofilament subunit proteins that co-assemble to form neurofilaments in vivo. Prior studies on cultured cells have shown that CMT2E/1F mutations disrupt neurofilament assembly and lead to protein aggregation, suggesting a possible disease mechanism. However, electron microscopy of axons in peripheral nerve biopsies from patients has revealed accumulations of neurofilament polymers of normal appearance and no evidence of protein aggregates. To reconcile these observations, we reexamined the assembly of seven CMT2E/1F NFL mutants in cultured cells. None of the mutants assembled into homopolymers in SW13vim- cells, but P8R, P22S, L268/269P, and P440/441L mutant NFL assembled into heteropolymers in the presence of neurofilament protein M (NFM) alone, and N98S, Q332/333P, and E396/397K mutant NFL assembled in the presence of NFM and peripherin. P8R, P22S, N98S, L268/269P, E396/397K, and P440/441L mutant NFL co-assembled into neurofilaments with endogenous NFL, NFM, and α-internexin in cultured neurons, although the N98S and E396/397K mutants showed reduced filament incorporation, and the Q332/333P mutant showed limited incorporation. We conclude that all the mutants are capable of assembling into neurofilaments, but for some of the mutants this was dependent on the identity of the other neurofilament proteins available for co-assembly, and most likely also their relative expression level. Thus, caution should be exercised when drawing conclusions about the assembly capacity of CMT2E/1F mutants based on transient transfections in cultured cells.
Topics: Charcot-Marie-Tooth Disease; Humans; Mutant Proteins; Mutation; Neurofilament Proteins
PubMed: 31574566
DOI: 10.1002/cm.21566 -
Current Opinion in Neurobiology Oct 1999Transgenic approaches have recently been used to investigate the functions of neuronal intermediate filaments. Gene knockout studies have demonstrated that... (Review)
Review
Transgenic approaches have recently been used to investigate the functions of neuronal intermediate filaments. Gene knockout studies have demonstrated that neurofilaments are not required for axogenesis and that individual neurofilament proteins play distinct roles in filament assembly and in the radial growth of axons. The involvement of neurofilaments in disease is supported by the discovery of novel mutations in the neurofilament heavy gene from cases of amyotrophic lateral sclerosis and by reports of neuronal death in mouse models expressing neurofilament and alpha-internexin transgenes. However, mouse studies have shown that axonal neurofilaments are not required for pathogenesis caused by mutations in superoxide dismutase and that increasing perikaryal levels of neurofilament proteins may even confer protection in this disease.
Topics: Animals; Gene Targeting; Health; Neurodegenerative Diseases; Neurofilament Proteins
PubMed: 10508735
DOI: 10.1016/S0959-4388(99)00004-5 -
Journal of Neurochemistry Sep 1993It is generally believed that the proteins of the nerve endings are synthesized on perikaryal polysomes and are eventually delivered to the presynaptic domain by...
It is generally believed that the proteins of the nerve endings are synthesized on perikaryal polysomes and are eventually delivered to the presynaptic domain by axoplasmic flow. At variance with this view, we have reported previously that a synaptosomal fraction from squid brain actively synthesizes proteins whose electrophoretic profile differs substantially from that of the proteins made in nerve cell bodies, axons, or glial cells, i.e., by the possible contaminants of the synaptosomal fraction. Using western analyses and immunoabsorption methods, we report now that (a) the translation products of the squid synaptosomal fraction include neurofilament (NF) proteins and (b) the electrophoretic pattern of the synaptosomal newly synthesized NF proteins is drastically different from that of the NF proteins synthesized by nerve cell bodies. The latter results exclude the possibility that NF proteins synthesized by the synaptosomal fraction originate in fragments of nerve cell bodies possibly contaminating the synaptosomal fraction. They rather indicate that in squid brain, nerve terminals synthesize NF proteins.
Topics: Animals; Blotting, Western; Brain; Decapodiformes; Electrophoresis, Polyacrylamide Gel; Immunologic Techniques; Molecular Weight; Nerve Endings; Neurofilament Proteins
PubMed: 8360679
DOI: 10.1111/j.1471-4159.1993.tb03632.x -
Journal of Neurocytology 2000Neurofilament proteins, a major intermediate filament component of the neuronal cytoskeleton, are organized as 10 nm thick filaments in axons and dendrites. They are... (Review)
Review
Neurofilament proteins, a major intermediate filament component of the neuronal cytoskeleton, are organized as 10 nm thick filaments in axons and dendrites. They are large, abundantly phosphorylated proteins with numerous phosphate acceptor sites, up to 100 in some cases, organized as numerous repeat motifs. Together with other cytoskeletal components such as microtubules, MAPs, actin and plectin-like linking molecules, they make up a dynamic lattice that sustains neuronal function from neuronal "birthday" to apoptotic cell death. The activity of the neuronal cytoskeleton is regulated by phosphorylation, dephosphorylation reactions mediated by numerous associated kinases, phosphatases and their regulators. Factors regulating multisite phosphorylation of NFs are topographically localized, with maximum phosphorylation of NF proteins consigned to axons. Phosphorylation defines the nature of NF interactions with one another and with other cytoskeletal components such as microtubules, MAPs and actin. To understand how these functional interactions are regulated by phosphorylation we attempt to identify the relevant kinases and phosphatases, their specific targets and the factors modulating their activity. As an initial working model we propose that NF phosphorylation is regulated topographically in neurons by compartment-specific macromolecular complexes of substrates, kinases and phosphatases. This implies that axonal complexes differ structurally and functionally from those in cell bodies and dendrites. Such protein assemblies, by virtue of conformational changes within proteins, facilitate ordered, sequential multisite phosphorylations that modulate dynamic cytoskeletal interactions.
Topics: Animals; Cells, Cultured; Cytoskeleton; Gene Expression Regulation; Humans; Macromolecular Substances; Mice; Mice, Knockout; Models, Biological; Neurodegenerative Diseases; Neurofilament Proteins; Neurons; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Protein Structure, Tertiary
PubMed: 11466475
DOI: 10.1023/a:1010999509251