A review and analysis of the clinical literature on Charcot–Marie–Tooth disease caused by mutations in neurofilament protein L

Stone, Elizabeth J.; Kolb, Stephen J.; Brown, Anthony

doi:10.1002/cm.21676

Cited by 24 publications

(30 citation statements)

References 108 publications

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“…Mutations, dominant missense ( Mersiyanova et al, 2000 ; Yoshihara et al, 2002 ; Jordanova et al, 2003 ; Stone et al, 2019 ), and recessive nonsense ( Abe et al, 2009 ; Yum et al, 2009 ; Fu and Yuan, 2018 ; Sainio et al, 2018 ; Stone et al, 2019 ) in the neurofilament light ( NEFL ) gene cause Charcot–Marie–Tooth neuropathy (CMT), highlighting the important role of neurofilaments in motor and sensory neurons. To date, more than 25 dominant missense mutations causing CMT2E and six recessive nonsense mutations resulting in CMT1F are reported ( Stone et al, 2021 ). CMT2E and CMT1F are both characterized as slowly progressive, length-dependent axonal neuropathies with highly variable disease onset.…”

Section: Introductionmentioning

confidence: 99%

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Neurofilament Light Regulates Axon Caliber, Synaptic Activity, and Organelle Trafficking in Cultured Human Motor Neurons

Sainio

Rasila

Molchanova

et al. 2022

Front. Cell Dev. Biol.

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Neurofilament light (NFL) is one of the proteins forming multimeric neuron-specific intermediate filaments, neurofilaments, which fill the axonal cytoplasm, establish caliber growth, and provide structural support. Dominant missense mutations and recessive nonsense mutations in the neurofilament light gene (NEFL) are among the causes of Charcot–Marie–Tooth (CMT) neuropathy, which affects the peripheral nerves with the longest axons. We previously demonstrated that a neuropathy-causing homozygous nonsense mutation in NEFL led to the absence of NFL in patient-specific neurons. To understand the disease-causing mechanisms, we investigate here the functional effects of NFL loss in human motor neurons differentiated from induced pluripotent stem cells (iPSC). We used genome editing to generate NEFL knockouts and compared them to patient-specific nonsense mutants and isogenic controls. iPSC lacking NFL differentiated efficiently into motor neurons with normal axon growth and regrowth after mechanical axotomy and contained neurofilaments. Electrophysiological analysis revealed that motor neurons without NFL fired spontaneous and evoked action potentials with similar characteristics as controls. However, we found that, in the absence of NFL, human motor neurons 1) had reduced axonal caliber, 2) the amplitude of miniature excitatory postsynaptic currents (mEPSC) was decreased, 3) neurofilament heavy (NFH) levels were reduced and no compensatory increases in other filament subunits were observed, and 4) the movement of mitochondria and to a lesser extent lysosomes was increased. Our findings elaborate the functional roles of NFL in human motor neurons. NFL is not only a structural protein forming neurofilaments and filling the axonal cytoplasm, but our study supports the role of NFL in the regulation of synaptic transmission and organelle trafficking. To rescue the NFL deficiency in the patient-specific nonsense mutant motor neurons, we used three drugs, amlexanox, ataluren (PTC-124), and gentamicin to induce translational read-through or inhibit nonsense-mediated decay. However, the drugs failed to increase the amount of NFL protein to detectable levels and were toxic to iPSC-derived motor neurons.

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Section: Introductionmentioning

confidence: 99%

“…Symptoms include distal muscle weakness and atrophy. Patients with recessive CMT1F have reduced nerve conduction velocity and are, therefore, characterized as demyelinating even though myelin loss is not the primary cause of symptoms ( Stone et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Neurofilament Light Regulates Axon Caliber, Synaptic Activity, and Organelle Trafficking in Cultured Human Motor Neurons

Sainio

Rasila

Molchanova

et al. 2022

Front. Cell Dev. Biol.

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“…Even though the exact function of Nfs continues to be concealed, they are assumed to play a predominant role in axon stability 236 contributing to adequate nerve conduction velocity 237 , and in recent years it has been proven that Nfs also engage in appropriate synapse functioning as well 238 . Mutations in genes encoding neurofilaments or causing neurofilament accumulation and aggregation have been linked to several diseases of the CNS and PNS characterised by axonal dysfunction and neurodegeneration, such as Parkinson disease (PD), amyotrophic lateral sclerosis (ALS) 239 and Charcot-Marie-Tooth disease 240 . Fundamentally, any pathophysiological process or disease resulting in axonal damage, whether it is acute or chronic in character, can result in increased levels of Nfs.…”

Section: Neurofilament Proteins -Backgroundmentioning

confidence: 99%

Emerging Biomarkers of Multiple Sclerosis in the Blood and the CSF: a Comprehensive Review of the Literature with a Focus on Neurofilaments and Therapeutic Considerations

Biernacki¹,

Kokas²,

Sandi³

et al. 2022

Preprint

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Introduction: multiple sclerosis (MS) is the most common immune-mediated chronic neurodegenerative disease of the central nervous system (CNS), affecting young people. Due to the permanent disability, cognitive impairment, and the enormous detrimental impact MS can exert on the patients’ health-related quality of life. It is of great importance to recognise it in time and commence adequate treatment at an early stage. The currently used disease-modifying therapies (DMT) aim to reduce disease activity and thus halt disability development, which in current clinical practice are monitored by clinical and imaging parameters but not by biomarkers found in blood and/or the cerebrospinal fluid (CSF). Both clinical and radiological measures routinely used to monitor disease activity lack information on the fundamental pathophysiological features and mechanisms of MS. Furthermore, they lag behind the disease process itself. By the time a clinical relapse becomes evident or a new lesion appears on the MRI scan, potentially irreversible damage has already occurred in the CNS. In recent years several biomarkers that previously have been linked to other neurological and immunological diseases have received increased attention in MS. Additionally, other novel, potential biomarkers with prognostic and diagnostic properties have been detected in the CSF and blood of MS patients. Areas covered: in this review, we summarise the most up to date knowledge and research conducted on the already known and most promising new biomarker candidates found in the CSF and blood of MS patients. Author commentary: the current diagnostic criteria of MS rely on three pillars; MRI imaging, clinical events and the presence of oligoclonal bands in the CSF (which was reinstated into the diagnostic criteria by the most recent revision). Even though the most recent McDonald criteria made the diagnosis of MS faster than the prior iteration, it is still not an infallible diagnostic toolset, especially at the very early stage of clinically isolated syndrome. Together with the gold standard MRI and clinical measures, ancillary blood and CSF biomarkers may not just improve diagnostic accuracy and speed but very well may become agents to monitor therapeutic efficacy and make even more personalised treatment in MS a reality in the near future. The major disadvantage of these biomarkers in the past has been the need to obtain CSF to measure them. However, the recent advances in extremely sensitive immunoassays made their measurement possible from peripheral blood even when present only in minuscule concentrations. This should mark the beginning of a new biomarker research and utilisation era in MS.

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“…Moreover, NF-L assembly state and functions are perturbed in a range of nervous system disorders. NEFL mutations cause some subtypes of Charcot-Marie-Tooth (CMT) disease 21,22 , an inherited peripheral neuropathy characterized by progressive atrophy of the distal limb muscles that leads to sensory loss and tendon reflex defects 23 . CMT-causative mutations in NEFL or other genes result in NF aggregation and aberrant motility of neuronal mitochondria 24-30 , underlining the physiological importance of NF-L function.…”

Section: Introductionmentioning

confidence: 99%

O-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations

Huynh

Schneider

et al. 2023

Preprint

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The neurofilament (NF) cytoskeleton is critical for neuronal morphology and function. In particular, the neurofilament-light (NF-L) subunit is required for NF assembly in vivo and is mutated in subtypes of Charcot-Marie-Tooth (CMT) disease. NFs are highly dynamic, and the regulation of NF assembly state is incompletely understood. Here, we demonstrate that human NF-L is modified in a nutrient-sensitive manner by O-linked-β-N-acetylglucosamine (O-GlcNAc), a ubiquitous form of intracellular glycosylation. We identify five NF-L O-GlcNAc sites and show that they regulate NF assembly state. Interestingly, NF-L engages in O-GlcNAc-mediated protein-protein interactions with itself and with the NF component α-internexin, implying that O-GlcNAc is a general regulator of NF architecture. We further show that NF-L O-GlcNAcylation is required for normal organelle trafficking in primary neurons, underlining its functional significance. Finally, several CMT-causative NF-L mutants exhibit perturbed O-GlcNAc levels and resist the effects of O-GlcNAcylation on NF assembly state, indicating a potential link between dysregulated O-GlcNAcylation and pathological NF aggregation. Our results demonstrate that site-specific glycosylation regulates NF-L assembly and function, and aberrant NF O-GlcNAcylation may contribute to CMT and other neurodegenerative disorders.

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A review and analysis of the clinical literature on Charcot–Marie–Tooth disease caused by mutations in neurofilament protein L

Cited by 24 publications

References 108 publications

Neurofilament Light Regulates Axon Caliber, Synaptic Activity, and Organelle Trafficking in Cultured Human Motor Neurons

Neurofilament Light Regulates Axon Caliber, Synaptic Activity, and Organelle Trafficking in Cultured Human Motor Neurons

Emerging Biomarkers of Multiple Sclerosis in the Blood and the CSF: a Comprehensive Review of the Literature with a Focus on Neurofilaments and Therapeutic Considerations

O-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations

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