Neurofilament Proteins as Prognostic Biomarkers in Neurological Disorders

Author(s): Yichen Lee, Bo H. Lee, William Yip, Pingchen Chou, Bak-Sau Yip*

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 43 , 2019

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Abstract:

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.

Keywords: Neurofilament, intermediate filament, biomarker, cerebrospinal fluid, mass spectrometry, nervous system disorders.

[1]
Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001; 69(3): 89-95.
[http://dx.doi.org/10.1067/mcp.2001.113989] [PMID: 11240971]
[2]
Strimbu K, Tavel JA. What are biomarkers? Curr Opin HIV AIDS 2010; 5(6): 463-6.
[http://dx.doi.org/10.1097/COH.0b013e32833ed177] [PMID: 20978388]
[3]
Janmey PA, Leterrier JF, Herrmann H. Assembly and structure of neurofilaments. Curr Opin Colloid Interface Sci 2003; 8(1): 40-7.
[http://dx.doi.org/10.1016/S1359-0294(03)00010-4]
[4]
Dahlstrand J, Zimmerman LB, McKay RD, Lendahl U. Characterization of the human nestin gene reveals a close evolutionary relationship to neurofilaments. J Cell Sci 1992; 103(Pt. 2): 589-97.
[PMID: 1478958]
[5]
Michalczyk K, Ziman M. Nestin structure and predicted function in cellular cytoskeletal organisation. Histol Histopathol 2005; 20(2): 665-71.
[PMID: 15736068]
[6]
Guérette D, Khan PA, Savard PE, Vincent M. Molecular evolution of type VI intermediate filament proteins. BMC Evol Biol 2007; 7: 164.
[http://dx.doi.org/10.1186/1471-2148-7-164] [PMID: 17854500]
[7]
Yuan A, Rao MV. Veeranna, Nixon RA. Neurofilaments at a glance. J Cell Sci 2012; 125(Pt. 14): 3257-63.
[http://dx.doi.org/10.1242/jcs.104729] [PMID: 22956720]
[8]
Nixon RA, Marotta CA. Degradation of neurofilament proteins by purified human brain cathepsin D. J Neurochem 1984; 43(2): 507-16.
[http://dx.doi.org/10.1111/j.1471-4159.1984.tb00928.x] [PMID: 6429280]
[9]
Hollenbeck PJ, Bray D. Rapidly transported organelles containing membrane and cytoskeletal components: their relation to axonal growth. J Cell Biol 1987; 105(6 Pt. 1): 2827-35.
[http://dx.doi.org/10.1083/jcb.105.6.2827] [PMID: 3693400]
[10]
Pant HC. Dephosphorylation of neurofilament proteins enhances their susceptibility to degradation by calpain. Biochem J 1988; 256(2): 665-8.
[http://dx.doi.org/10.1042/bj2560665] [PMID: 2851997]
[11]
Jaffe H. Veeranna, Pant HC. Characterization of serine and threonine phosphorylation sites in beta-elimination/ethanethiol addition-modified proteins by electrospray tandem mass spectrometry and database searching. Biochemistry 1998; 37(46): 16211-24.
[http://dx.doi.org/10.1021/bi981264p] [PMID: 9819213]
[12]
Julien JP, Mushynski WE. Multiple phosphorylation sites in mammalian neurofilament polypeptides. J Biol Chem 1982; 257(17): 10467-70.
[PMID: 7202005]
[13]
Koel-Simmelink MJ, Vennegoor A, Killestein J, et al. The impact of pre-analytical variables on the stability of neurofilament proteins in CSF, determined by a novel validated SinglePlex Luminex assay and ELISA. J Immunol Methods 2014; 402(1-2): 43-9.
[http://dx.doi.org/10.1016/j.jim.2013.11.008] [PMID: 24275679]
[14]
Petzold A, Keir G, Green AJ, Giovannoni G, Thompson EJ. A specific ELISA for measuring neurofilament heavy chain phosphoforms. J Immunol Methods 2003; 278(1-2): 179-90.
[http://dx.doi.org/10.1016/S0022-1759(03)00189-3] [PMID: 12957406]
[15]
Petzold A, Shaw G. Comparison of two ELISA methods for measuring levels of the phosphorylated neurofilament heavy chain. J Immunol Methods 2007; 319(1-2): 34-40.
[http://dx.doi.org/10.1016/j.jim.2006.09.021] [PMID: 17140597]
[16]
Kuhle J, Barro C, Andreasson U, et al. Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa. Clin Chem Lab Med 2016; 54(10): 1655-61.
[http://dx.doi.org/10.1515/cclm-2015-1195] [PMID: 27071153]
[17]
Fotenos AF, Snyder AZ, Girton LE, Morris JC, Buckner RL. Normative estimates of cross-sectional and longitudinal brain volume decline in aging and AD. Neurology 2005; 64(6): 1032-9.
[http://dx.doi.org/10.1212/01.WNL.0000154530.72969.11] [PMID: 15781822]
[18]
Lu CH, Petzold A, Kalmar B, Dick J, Malaspina A, Greensmith L. Plasma neurofilament heavy chain levels correlate to markers of late stage disease progression and treatment response in SOD1(G93A) mice that model ALS. PLoS One 2012; 7(7) e40998
[http://dx.doi.org/10.1371/journal.pone.0040998] [PMID: 22815892]
[19]
Weydt P, Oeckl P, Huss A, et al. Neurofilament levels as biomarkers in asymptomatic and symptomatic familial amyotrophic lateral sclerosis. Ann Neurol 2016; 79(1): 152-8.
[http://dx.doi.org/10.1002/ana.24552] [PMID: 26528863]
[20]
Ganesalingam J, An J, Shaw CE, Shaw G, Lacomis D, Bowser R. Combination of neurofilament heavy chain and complement C3 as CSF biomarkers for ALS. J Neurochem 2011; 117(3): 528-37.
[http://dx.doi.org/10.1111/j.1471-4159.2011.07224.x] [PMID: 21418221]
[21]
Fernyhough P, Schmidt RE. Neurofilaments in diabetic neuropathy. Int Rev Neurobiol 2002; 50: 115-44.
[http://dx.doi.org/10.1016/S0074-7742(02)50075-1] [PMID: 12198808]
[22]
Lin YS, Lee WJ, Wang SJ, Fuh JL. Levels of plasma neurofilament light chain and cognitive function in patients with Alzheimer or Parkinson disease. Sci Rep 2018; 8(1): 17368.
[http://dx.doi.org/10.1038/s41598-018-35766-w] [PMID: 30478269]
[23]
Singh P, Yan J, Hull R, et al. Levels of phosphorylated axonal neurofilament subunit H (pNfH) are increased in acute ischemic stroke. J Neurol Sci 2011; 304(1-2): 117-21.
[http://dx.doi.org/10.1016/j.jns.2011.01.025] [PMID: 21349546]
[24]
Vågberg M, Norgren N, Dring A, et al. Levels and age dependency of neurofilament light and glial fibrillary acidic protein in healthy individuals and their relation to the brain parenchymal fraction. PLoS One 2015; 10(8) e0135886
[http://dx.doi.org/10.1371/journal.pone.0135886] [PMID: 26317831]
[25]
Poesen K, Van Damme P. Diagnostic and Prognostic Performance of Neurofilaments in ALS. Front Neurol 2019; 9: 1167.
[http://dx.doi.org/10.3389/fneur.2018.01167] [PMID: 30713520]
[26]
Kušnierová P, Zeman D, Hradílek P, Čábal M, Zapletalová O. Neurofilament levels in patients with neurological diseases: a comparison of neurofilament light and heavy chain levels. J Clin Lab Anal 2019; 33(7) e22948
[http://dx.doi.org/10.1002/jcla.22948] [PMID: 31199010]
[27]
Reijn TS, Abdo WF, Schelhaas HJ, Verbeek MM. CSF neurofilament protein analysis in the differential diagnosis of ALS. J Neurol 2009; 256(4): 615-9.
[http://dx.doi.org/10.1007/s00415-009-0131-z] [PMID: 19296046]
[28]
Lu CH, Petzold A, Topping J, et al. Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study. J Neurol Neurosurg Psychiatry 2015; 86(5): 565-73.
[http://dx.doi.org/10.1136/jnnp-2014-307672] [PMID: 25009280]
[29]
Håkansson I, Tisell A, Cassel P, et al. Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis. J Neuroinflammation 2018; 15(1): 209.
[http://dx.doi.org/10.1186/s12974-018-1249-7] [PMID: 30021640]
[30]
Novakova L, Zetterberg H, Sundström P, et al. Monitoring disease activity in multiple sclerosis using serum neurofilament light protein. Neurology 2017; 89(22): 2230-7.
[http://dx.doi.org/10.1212/WNL.0000000000004683] [PMID: 29079686]
[31]
Katsavos S, Anagnostouli M. Biomarkers in multiple sclerosis: an up-to-date overview. Mult Scler Int 2013; 2013: 340-508.
[http://dx.doi.org/10.1155/2013/340508] [PMID: 23401777]
[32]
Ganesalingam J, Bowser R. The application of biomarkers in clinical trials for motor neuron disease. Biomarkers Med 2010; 4(2): 281-97.
[http://dx.doi.org/10.2217/bmm.09.71] [PMID: 20406070]
[33]
Solfrizzi V, Panza F, Colacicco AM, et al. Vascular risk factors, incidence of MCI, and rates of progression to dementia. Neurology 2004; 63(10): 1882-91.
[http://dx.doi.org/10.1212/01.WNL.0000144281.38555.E3] [PMID: 15557506]
[34]
Goldman JG, Litvan I. Mild cognitive impairment in Parkinson’s disease. Minerva Med 2011; 102(6): 441-59.
[PMID: 22193376]
[35]
Hall S, Öhrfelt A, Constantinescu R, et al. Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch Neurol 2012; 69(11): 1445-52.
[http://dx.doi.org/10.1001/archneurol.2012.1654] [PMID: 22925882]
[36]
Hansson O, Janelidze S, Hall S, et al. Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder. Neurology 2017; 88(10): 930-7.
[http://dx.doi.org/10.1212/WNL.0000000000003680] [PMID: 28179466]
[37]
Sandelius Å, Zetterberg H, Blennow K, et al. Plasma neurofilament light chain concentration in the inherited peripheral neuropathies. Neurology 2018; 90(6): e518-24.
[http://dx.doi.org/10.1212/WNL.0000000000004932] [PMID: 29321234]
[38]
Rossor AM, Lu CH, Petzold A, et al. Plasma neurofilament heavy chain is not a useful biomarker in charcot-marie-tooth disease. Muscle Nerve 2016; 53(6): 972-5.
[http://dx.doi.org/10.1002/mus.25124] [PMID: 27015106]
[39]
Jin HY, Park TS. Role of inflammatory biomarkers in diabetic peripheral neuropathy. J Diabetes Investig 2018; 9(5): 1016-8.
[http://dx.doi.org/10.1111/jdi.12794] [PMID: 29277966]
[40]
Qiao X, Zhang S, Zhao W, et al. Serum phosphorylated neurofilament-heavy chain, a potential biomarker, is associated with peripheral neuropathy in patients with Type 2 Diabetes. Medicine (Baltimore) 2015; 94(44) e1908
[http://dx.doi.org/10.1097/MD.0000000000001908] [PMID: 26554790]
[41]
Nakano Y, Kanda T. Pathology of Guillain-Barre syndrome. Clin Exp Neuroimmunol 2016; 7: 312-9.
[http://dx.doi.org/10.1111/cen3.12342]
[42]
Ubogu EE. Inflammatory neuropathies: pathology, molecular markers and targets for specific therapeutic intervention. Acta Neuropathol 2015; 130(4): 445-68.
[http://dx.doi.org/10.1007/s00401-015-1466-4] [PMID: 26264608]
[43]
Mariotto S, Farinazzo A, Magliozzi R, Alberti D, Monaco S, Ferrari S. Serum and cerebrospinal neurofilament light chain levels in patients with acquired peripheral neuropathies. J Peripher Nerv Syst 2018; 23(3): 174-7.
[http://dx.doi.org/10.1111/jns.12279] [PMID: 29974556]
[44]
Al Nimer F, Thelin E, Nyström H, et al. Comparative assessment of the prognostic value of biomarkers in traumatic brain injury reveals an independent role for serum levels of neurofilament light. PLoS One 2015; 10(7) e0132177
[http://dx.doi.org/10.1371/journal.pone.0132177] [PMID: 26136237]
[45]
Wallace C, Zetterberg H, Blennow K, van Donkelaar P. No change in plasma tau and serum neurofilament light concentrations in adolescent athletes following sport-related concussion. PLoS One 2018; 13(10) e0206466
[http://dx.doi.org/10.1371/journal.pone.0206466] [PMID: 30372457]
[46]
Verde F, Steinacker P, Weishaupt JH, et al. Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2019; 90(2): 157-64.
[http://dx.doi.org/10.1136/jnnp-2018-318704] [PMID: 30309882]
[47]
Lewczuk P, Ermann N, Andreasson U, et al. Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer’s disease. Alzheimers Res Ther 2018; 10(1): 71.
[48]
Shahim P, Zetterberg H, Tegner Y, Blennow K. Serum neurofilament light as a biomarker for mild traumatic brain injury in contact sports. Neurology 2017; 88(19): 1788-94.
[http://dx.doi.org/10.1212/WNL.0000000000003912]


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VOLUME: 25
ISSUE: 43
Year: 2019
Page: [4560 - 4569]
Pages: 10
DOI: 10.2174/1381612825666191210154535
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