The Evolution of Neurofilament Light Chain in Multiple Sclerosis

Ferreira‐Atuesta, Carolina; Reyes, Saúl; Giovanonni, Gavin; Gnanapavan, Sharmilee

doi:10.3389/fnins.2021.642384

Cited by 85 publications

(71 citation statements)

References 165 publications

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“…Therefore, NF-L is suggested to be a pan-biomarker of chronic or acute neurological damage. The two major applications that are now emerging are, first, in the follow-up of long-term diseases such as multiple sclerosis [ 12 ] and, second, in the differentiation between neurological and psychological disorders [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Neurofilament light chain concentration in an aging population

et al. 2022

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Background Neurofilament light chain (NF-L) concentration is recognized to be modified in neurological diseases and traumatic brain injuries, but studies in the normal aging population are lacking. It is, therefore, urgent to identify influencing factors of NF-L concentration in the aging population. Method We assessed NF-L concentration in sera of a large cohort of 409 community-dwelling adults aged over 65 years. We studied the association between NF-L and various physiological factors but also with self-reported comorbidities or life-style habits. Results We showed that NF-L concentration in serum was tightly associated with cystatin C concentration (r = 0.501, p < 0.0001) and consequently, to the estimated glomerular filtration rate (eGFR) (r = − 0.492; p < 0.0001). Additionally, NF-L concentration was dependent on age and body mass index (BMI) but not sex. Among the self-reported comorbidities, subjects who reported neurological disorders, cardiovascular diseases or history of fracture had higher NF-L concentration in univariate analysis, whereas it was only the case for subjects who reported neurological disorders in the multivariate analysis. NF-L concentration was also increased when Mini-Mental State Examination (MMSE) was decreased (≤ 25 points) but not when geriatric depression score (GDS) was increased (> 5 points) in both univariate and multivariate analysis. Finally, we are providing reference ranges by age categories for subjects with or without altered renal function. Conclusion NF-L concentration in the aging population is not driven by the increasing number of comorbidities or depression. Yet, NF-L blood concentration is dependent on kidney function and NF-L interpretation in patients suffering from renal failure should be taken with caution.

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Section: Introductionmentioning

confidence: 99%

Neurofilament light chain concentration in an aging population

et al. 2022

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“…Accumulations of neurofilaments are a pathological feature of several neurodegenerative diseases ( Didonna and Opal, 2019 ), including amyotrophic lateral sclerosis (ALS), Alzheimer’s, and Parkinson’s diseases. Moreover, NFL as a highly abundant protein in neurons shows promise as a serum biomarker for neuronal disruption in various neurological diseases, such as ALS ( Verde et al, 2021 ) and multiple sclerosis ( Ferreira-Atuesta 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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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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“…However, the overall ability to predict different clinical courses of the disease, and its response to treatment, is still very limited. There is increasing evidence showing that the levels of neurofilament light chain in the CSF and serum can be used as indicators of prognosis and response to treatment in MS patients [ 7 , 8 ]. However, there is still an emerging need to further characterize the disease by simple and reliable laboratory tests, not only to describe clinical disease activity at a given timepoint, but ideally also to be able to predict the future development, in response or not to treatment, of this disabling and partially asymptomatic disease [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Posttranslational modifications of proteins are key features in the identification of CSF biomarkers of multiple sclerosis

Salazar

Lourenco

Manadas

et al. 2022

J Neuroinflammation

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Background Multiple sclerosis is an inflammatory and degenerative disease of the central nervous system (CNS) characterized by demyelination and concomitant axonal loss. The lack of a single specific test, and the similarity to other inflammatory diseases of the central nervous system, makes it difficult to have a clear diagnosis of multiple sclerosis. Therefore, laboratory tests that allows a clear and definite diagnosis, as well as to predict the different clinical courses of the disease are of utmost importance. Herein, we compared the cerebrospinal fluid (CSF) proteome of patients with multiple sclerosis (in the relapse–remitting phase of the disease) and other diseases of the CNS (inflammatory and non-inflammatory) aiming at identifying reliable biomarkers of multiple sclerosis. Methods CSF samples from the discovery group were resolved by 2D-gel electrophoresis followed by identification of the protein spots by mass spectrometry. The results were analyzed using univariate (Student’s t test) and multivariate (Hierarchical Cluster Analysis, Principal Component Analysis, Linear Discriminant Analysis) statistical and numerical techniques, to identify a set of protein spots that were differentially expressed in CSF samples from patients with multiple sclerosis when compared with other two groups. Validation of the results was performed in samples from a different set of patients using quantitative (e.g., ELISA) and semi-quantitative (e.g., Western Blot) experimental approaches. Results Analysis of the 2D-gels showed 13 protein spots that were differentially expressed in the three groups of patients: Alpha-1-antichymotrypsin, Prostaglandin-H2-isomerase, Retinol binding protein 4, Transthyretin (TTR), Apolipoprotein E, Gelsolin, Angiotensinogen, Agrin, Serum albumin, Myosin-15, Apolipoprotein B-100 and EF-hand calcium-binding domain—containing protein. ELISA experiments allowed validating part of the results obtained in the proteomics analysis and showed that some of the alterations in the CSF proteome are also mirrored in serum samples from multiple sclerosis patients. CSF of multiple sclerosis patients was characterized by TTR oligomerization, thus highlighting the importance of analyzing posttranslational modifications of the proteome in the identification of novel biomarkers of the disease. Conclusions The model built based on the results obtained upon analysis of the 2D-gels and in the validation phase attained an accuracy of about 80% in distinguishing multiple sclerosis patients and the other two groups.

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The Evolution of Neurofilament Light Chain in Multiple Sclerosis

Cited by 85 publications

References 165 publications

Neurofilament light chain concentration in an aging population

Neurofilament light chain concentration in an aging population

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

Posttranslational modifications of proteins are key features in the identification of CSF biomarkers of multiple sclerosis

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