The role of neurofilament aggregation in neurodegeneration: lessons from rare inherited neurological disorders

Didonna, Alessandro; Opal, Puneet

doi:10.1186/s13024-019-0318-4

Cited by 100 publications

(100 citation statements)

References 122 publications

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“…Phosphorylation, other than conferring resistance to proteases [28], contributes to generate the neurofibrillary structure of the protein. Indeed, phosphorylation of the head domain regulates NF polymerization, whereas that of the tail mediates the spacing between NF polymers in both NfM and NfH [29,30]. These processes are thought to occur in sequential steps in different regions of the neurons, with the head domain being phosphorylated in the cell body, and the tail domain only after the protein reach the axon [29].…”

Section: Nf Structure and Compositionmentioning

confidence: 99%

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

Zucchi

Bonetto

Sorarù

et al. 2020

Mol Neurodegeneration

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Motor neuron diseases (MNDs) are etiologically and biologically heterogeneous diseases. The pathobiology of motor neuron degeneration is still largely unknown, and no effective therapy is available. Heterogeneity and lack of specific disease biomarkers have been appointed as leading reasons for past clinical trial failure, and biomarker discovery is pivotal in today’s MND research agenda. In the last decade, neurofilaments (NFs) have emerged as promising biomarkers for the clinical assessment of neurodegeneration. NFs are scaffolding proteins with predominant structural functions contributing to the axonal cytoskeleton of myelinated axons. NFs are released in CSF and peripheral blood as a consequence of axonal degeneration, irrespective of the primary causal event. Due to the current availability of highly-sensitive automated technologies capable of precisely quantify proteins in biofluids in the femtomolar range, it is now possible to reliably measure NFs not only in CSF but also in blood. In this review, we will discuss how NFs are impacting research and clinical management in ALS and other MNDs. Besides contributing to the diagnosis at early stages by differentiating between MNDs with different clinical evolution and severity, NFs may provide a useful tool for the early enrolment of patients in clinical trials. Due to their stability across the disease, NFs convey prognostic information and, on a larger scale, help to stratify patients in homogenous groups. Shortcomings of NFs assessment in biofluids will also be discussed according to the available literature in the attempt to predict the most appropriate use of the biomarker in the MND clinic.

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Section: Nf Structure and Compositionmentioning

confidence: 99%

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

Zucchi

Bonetto

Sorarù

et al. 2020

Mol Neurodegeneration

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“…As their presence within the CSF is specific for axonal injury, elevated NFL concentrations have been widely reported in neurodegenerative disorders, especially in AD patients [ 59 , 62 , 63 , 64 ]. While the mechanisms of NFL aggregation are still unelucidated, they are thought to be similar to the hyperphosphorylation process of tau proteins [ 65 ].…”

Section: Cerebrospinal Fluid Biomarkersmentioning

confidence: 99%

Body Fluid Biomarkers for Alzheimer’s Disease—An Up-To-Date Overview

2020

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Neurodegeneration is a highly complex process which is associated with a variety of molecular mechanisms related to ageing. Among neurodegenerative disorders, Alzheimer’s disease (AD) is the most common, affecting more than 45 million individuals. The underlying mechanisms involve amyloid plaques and neurofibrillary tangles (NFTs) deposition, which will subsequently lead to oxidative stress, chronic neuroinflammation, neuron dysfunction, and neurodegeneration. The current diagnosis methods are still limited in regard to the possibility of the accurate and early detection of the diseases. Therefore, research has shifted towards the identification of novel biomarkers and matrices as biomarker sources, beyond amyloid-β and tau protein levels within the cerebrospinal fluid (CSF), that could improve AD diagnosis. In this context, the aim of this paper is to provide an overview of both conventional and novel biomarkers for AD found within body fluids, including CSF, blood, saliva, urine, tears, and olfactory fluids.

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“…In ALS, the abnormal deposition of hyper-phosphorylated forms of NFs has been detected in MNs [22]- [24].The importance NEFL in ALS is supported by the following evidence. First, high levels of NEFL protein are detected in cerebrospinal fluid (CSF) and blood of all ALS cases [25] as early as 12 months before the onset of the disease [26].…”

Section: Introductionmentioning

confidence: 66%

Functional characterization of Neurofilament Light b splicing andmisbalance in zebrafish

Demy

Campanari

Munoz-Ruiz

et al. 2020

Preprint

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Neurofilaments (NFs), a major cytoskeletal component of motor neurons, play a key role in their differentiation, establishment and maintenance of their morphology and mechanical strength. The de novo assembly of these neuronal intermediate filaments requires the presence of the neurofilament light subunit, NEFL, which expression is reduced in motor neurons in Amyotrophic Lateral Sclerosis (ALS). This study used zebrafish as a model to characterize the NEFL homologue neflb, which encodes two different isoforms via splicing of the primary transcript (neflbE4 and neflbE3). In vivo imaging showed that neflb is crucial for proper neuronal development, and that disrupting the balance between its two isoforms specifically affects NF assembly and motor axon growth, with resulting motor deficits. This equilibrium is also disrupted upon partial depletion of TDP-43, a RNA binding protein that is mislocalized into cytoplasmic inclusions in ALS. The study supports interaction of NEFL expression and splicing with TDP-43 in a common pathway, both biologically and pathogenetically.

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The role of neurofilament aggregation in neurodegeneration: lessons from rare inherited neurological disorders

Cited by 100 publications

References 122 publications

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

Body Fluid Biomarkers for Alzheimer’s Disease—An Up-To-Date Overview

Functional characterization of Neurofilament Light b splicing andmisbalance in zebrafish

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