2,161
Views
1
CrossRef citations to date
0
Altmetric
Review

Advancing mechanistic understanding and biomarker development in amyotrophic lateral sclerosis

ORCID Icon, ORCID Icon, , ORCID Icon, ORCID Icon, ORCID Icon, & ORCID Icon show all
Pages 977-994 | Received 08 Jul 2021, Accepted 08 Nov 2021, Published online: 02 Dec 2021

References

  • Hardiman O, Al-Chalabi A, and Chio A, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;5 (3):7071.
  • Renton AE, Chiò A, and Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci. . 2014;17 (1):17–23.
  • Al-Chalabi A, Fang F, and Hanby MF, et al. An estimate of amyotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry . 2010;81(12):1324–1326.
  • van Blitterswijk M, van Es MA, and Hennekam EA, et al. Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum Mol Genet . 2012;21(17):3776–3784.
  • Zou ZY, Zhou ZR, and Che CH, et al. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry . 2017;88(7):540–549.
  • Taylor JP, Brown RHJ, and Cleveland DW. Decoding ALS: from genes to mechanism. Nature. . 2016;539(7628):197–206.
  • Talbot K, Feneberg E, Scaber J, et al. Amyotrophic lateral sclerosis: the complex path to precision medicine. J Neurol. 2018;265(10):2454–2462.
  • Al-Chalabi A, Calvo A, and Chio A, et al. Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study. Lancet Neurol . 2014;13(11):1108–1113.
  • Neumann M, Sampathu DM, and Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science . 2006;314(5796):130–133.
  • Aebersold R, Mann M. Mass-spectrometric exploration of proteome structure and function. Nature. 2016;537(7620):347–355.
  • Laferrière F, Maniecka Z, Pérez-Berlanga M, et al. TDP-43 extracted from frontotemporal lobar degeneration subject brains displays distinct aggregate assemblies and neurotoxic effects reflecting disease progression rates. Nat Neurosci. 2019;22(1):65–77.
  • Feneberg E, Gray E, and Ansorge O, et al. Towards a TDP-43-Based Biomarker for ALS and FTLD. Mol Neurobiol . 2018; . ;55(10):7789–7801.
  • Igaz LM, Kwong LK, Xu Y, et al. Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Am J Pathol. 2008;173(1):182–194.
  • Alonso R, Pisa D, Marina AI, et al. Evidence for fungal infection in cerebrospinal fluid and brain tissue from patients with amyotrophic lateral sclerosis. Int J Biol Sci. 2015;11(5):546–558.
  • Vassileff N, Vella LJ, Rajapaksha H, et al. Revealing the proteome of motor cortex derived extracellular vesicles isolated from amyotrophic lateral sclerosis Human Postmortem Tissues. Cells. 2020;9(7):1709.
  • Iridoy MO, Zubiri I, and Zelaya MV , et al. Neuroanatomical quantitative proteomics reveals common pathogenic biological routes between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Int J Mol Sci. 2019; 20(1):4 .
  • Conti A, Riva N, Pesca M, et al. Increased expression of Myosin binding protein H in the skeletal muscle of amyotrophic lateral sclerosis patients. Biochim Biophys Acta - Mol Basis Dis. 2014;1842(1):99–106.
  • Elf K, Shevchenko G, Nygren I, et al. Alterations in muscle proteome of patients diagnosed with amyotrophic lateral sclerosis. J Proteomics. 2014;108:55–64.
  • Kametani F, Obi T, and Shishido T, et al. Mass spectrometric analysis of accumulated TDP-43 in amyotrophic lateral sclerosis brains. Sci Rep. 2016;6(1).
  • Feneberg E, Charles PD, and Finelli MJ, et al. Detection and quantification of novel C-terminal TDP-43 fragments in ALS-TDP. Brain Pathol. 2020; 31(4):e129 ;
  • Nonaka T, Kametani F, Arai T, et al. Truncation and pathogenic mutations facilitate the formation of intracellular aggregates of TDP-43. Hum Mol Genet. 2009;18(18):3353–3364.
  • Tomé SO, Vandenberghe R, Ospitalieri S, et al. Distinct molecular patterns of TDP-43 pathology in Alzheimer’s disease: relationship with clinical phenotypes. Acta Neuropathol Commun. 2020;8(1). DOI:https://doi.org/10.1186/s40478-020-00934-5.
  • Pobran TD, Yang D, Mackenzie IRA, et al. Aptamer-based enrichment of TDP-43 from human cells and tissues with quantification by HPLC-MS/MS. J Neurosci Methods. 2021;363:109344.
  • Strong MJ, Strong WL, Jaffe H, et al. Phosphorylation state of the native high-molecular-weight neurofilament subunit protein from cervical spinal cord in sporadic amyotrophic lateral sclerosis. J Neurochem. 2001;76(5):1315–1325.
  • Umoh ME, Dammer EB, and Dai J, et al. A proteomic network approach across the ALS-FTD disease spectrum resolves clinical phenotypes and genetic vulnerability in human brain. EMBO Mol Med. 2018;10(1):48–62.
  • Engelen-Lee J, Blokhuis AM, Spliet WGM, et al. Proteomic profiling of the spinal cord in ALS: decreased ATP5D levels suggest synaptic dysfunction in ALS pathogenesis. Amyotroph Lateral Scler Front Degener. 2017;18(3–4):210–220.
  • Liu D, Liu C, and Li J, et al. Proteomic analysis reveals differentially regulated protein acetylation in human amyotrophic lateral sclerosis spinal cord. PLoS One. 2013; 8(12):e779
  • Oeckl P, Weydt P, and Thal DR, et al. Proteomics in cerebrospinal fluid and spinal cord suggests UCHL1, MAP2 and GPNMB as biomarkers and underpins importance of transcriptional pathways in amyotrophic lateral sclerosis. Acta Neuropathol. 2020;139(1):119–134.
  • Volkening K, Keller BA, and Leystra-Lantz C, et al. RNA and Protein Interactors with TDP-43 in Human Spinal-Cord Lysates in Amyotrophic Lateral Sclerosis. J Proteome Res. 2018 17(4) 1712–29 ;
  • Hanrieder J, Ekegren T, Andersson M, et al. MALDI imaging of post-mortem human spinal cord in amyotrophic lateral sclerosis. J Neurochem. 2013;124(5):695–707.
  • Ekegren T, Hanrieder J, Aquilonius SM, et al. Focused proteomics in post-mortem human spinal cord. J Proteome Res. 2006;5(9):2364–2371.
  • Feneberg E, Gordon D, Thompson AG, et al. An ALS-linked mutation in TDP-43 disrupts normal protein interactions in the motor neuron response to oxidative stress. Neurobiol Dis. 2020;144:105050.
  • Freibaum BD, Chitta RK, and High AA, et al. Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J Proteome Res. 2010;9(2):1104–1120.
  • Davis SA, Itaman S, Khalid-Janney CM, et al. TDP-43 interacts with mitochondrial proteins critical for mitophagy and mitochondrial dynamics. Neurosci Lett. 2018;678:8–15.
  • Blokhuis AM, Koppers M, and Groen EJN, et al. Comparative interactomics analysis of different ALS-associated proteins identifies converging molecular pathways. Acta Neuropathol. 2016;132(2):175–196.
  • Kawaguchi T, Rollins MG, Moinpour M, et al. Changes to the TDP-43 and FUS Interactomes Induced by DNA Damage. J Proteome Res. 2020;19(1):360–370.
  • Kamelgarn M, Chen J, Kuang L, et al. Proteomic analysis of FUS interacting proteins provides insights into FUS function and its role in ALS. Biochim Biophys Acta - Mol Basis Dis. 2016;1862(10):2004–2014.
  • Sun S, Ling SC, and Qiu J, et al. ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP. Nat Commun. 2015; 6:6171 .
  • Wang T, Jiang X, Chen G, et al. Interaction of amyotrophic lateral sclerosis/frontotemporal lobar degeneration-associated fused-in-sarcoma with proteins involved in metabolic and protein degradation pathways. Neurobiol Aging. 2015;36(1):527–535.
  • Basso M, Samengo G, Nardo G, et al. Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis. PLoS One. 2009;4(12):e8130.
  • Shaw BF, Lelie HL, Durazo A, et al. Detergent-insoluble aggregates associated with amyotrophic lateral sclerosis in transgenic mice contain primarily full-length, unmodified superoxide dismutase-1. J Biol Chem. 2008;283(13):8340–8350.
  • Une M, Yamakawa M, Watanabe Y, et al. SOD1-interacting proteins: roles of aggregation cores and protein degradation systems. Neurosci Res. 2021;170:295–305.
  • Hans F, Eckert M, Von Zweydorf F, et al. Identification and characterization of ubiquitinylation sites in TAR DNA-binding protein of 43 kDa (TDP-43). J Biol Chem. 2018;293(41):16083–16099.
  • Monahan Z, Ryan VH, Janke AM, et al. Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity. EMBO J. 2017;36(20):2951–2967.
  • Cohen TJ, Hwang AW, and Restrepo CR, et al. An acetylation switch controls TDP-43 function and aggregation propensity. Nat Commun. 2015;6.
  • Tanikawa C, Ueda K, Suzuki A, et al. Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility. Cell Rep. 2018;22(6):1473–1483.
  • Niikura T, Kita Y, Abe Y. SUMO3 modification accelerates the aggregation of ALS-Linked SOD1 mutants. PLoS One. 2014;9(6):e101080.
  • Bruijn LI, Becher MW, Lee MK, et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron. 1997;18(2):327–338.
  • Gertsman I, Wuu J, and McAlonis-Downes M, et al. An endogenous peptide marker differentiates SOD1 stability and facilitates pharmacodynamic monitoring in SOD1 amyotrophic lateral sclerosis. JCI Insight. 2019;4(10). .
  • Shi Y, Rhodes NR, Abdolvahabi A, et al. Deamidation of asparagine to aspartate destabilizes Cu, Zn superoxide dismutase, accelerates fibrillization, and mirrors ALS-linked mutations. J Am Chem Soc. 2013;135(42):15897–15908.
  • Hutten S, Dormann D. RAN translation down. Nat Neurosci. 2019;22(9):1379–1380.
  • Radwan M, Ang CS, Ormsby AR, et al. Arginine in C9ORF72 dipolypeptides mediates promiscuous proteome binding and multiple modes of toxicity. Mol Cell Proteomics. 2020;19(4):640–654.
  • Moens TG, Niccoli T, Wilson KM, et al. C9orf72 arginine-rich dipeptide proteins interact with ribosomal proteins in vivo to induce a toxic translational arrest that is rescued by eIF1A. Acta Neuropathol. 2019;137(3):487–500.
  • Hartmann H, Hornburg D, Czuppa M, et al. Proteomics and C9orf72 neuropathology identify ribosomes as poly-GR/PR interactors driving toxicity. Life Sci Alliance. 2018;1(2):e201800070.
  • Kanekura K, Yagi T, Cammack AJ, et al. Poly-dipeptides encoded by the C9ORF72 repeats block global protein translation. Hum Mol Genet. 2016;25(9):1803–1813.
  • May S, Hornburg D, Schludi MH, et al. C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration. Acta Neuropathol. 2014;128(4):485–503.
  • Cooper-Knock J, Walsh MJ, and Higginbottom A, et al. Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain . 2014;137(7):2040–2051. .
  • Sivadasan R, Hornburg D, Drepper C, et al. C9ORF72 interaction with cofilin modulates actin dynamics in motor neurons. Nat Neurosci. 2016;19(12):1610–1618.
  • Ho WY, Tai YK, and Chang JC, et al. . In: Autophagy. 2019; 15(5):827–42 .
  • Farg MA, Sundaramoorthy V, Sultana JM, et al. C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet. 2014;23(13):3579–3595.
  • Li Q, Vande VC, Israelson A, et al. ALS-linked mutant superoxide dismutase 1 (SOD1) alters mitochondrial protein composition and decreases protein import. Proc Natl Acad Sci U S A. 2010;107(49):21146–21151.
  • Fukada K, Zhang F, Vien A, et al. Mitochondrial proteomic analysis of a cell line model of familial amyotrophic lateral sclerosis. Mol Cell Proteomics. 2004;3(12):1211–1223.
  • Allen S, Heath PR, Kirby J, et al. Analysis of the cytosolic proteome in a cell culture model of familial amyotrophic lateral sclerosis reveals alterations to the proteasome, antioxidant defenses, and nitric oxide synthetic pathways. J Biol Chem. 2003;278(8):6371–6383.
  • Di Poto C, Iadarola P, Bardoni AM, et al. 2-DE and MALDI-TOF-MS for a comparative analysis of proteins expressed in different cellular models of amyotrophical lateral sclerosis. Electrophoresis. 2007;28(23):4320–4329.
  • Shin JH, London J, Le Pecheur M, et al. Proteome analysis in hippocampus of mice overexpressing human Cu/Zn-superoxide dismutase 1. Neurochem Int. 2005;46(8):641–653.
  • Zhang K, Donnelly CJ, Haeusler AR, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015;525(7567):56–61.
  • Ortega JA, Daley EL, Kour S, et al. Nucleocytoplasmic Proteomic Analysis Uncovers eRF1 and Nonsense-Mediated Decay as Modifiers of ALS/FTD C9orf72 Toxicity. Neuron. 2020;106(1):90–107.e13.
  • Štalekar M, Yin X, Rebolj K, et al. Proteomic analyses reveal that loss of TDP-43 affects RNA processing and intracellular transport. Neuroscience. 2015;293:157–170.
  • Kim JE, Hong YH, and Kim JY, et al. Altered nucleocytoplasmic proteome and transcriptome distributions in an in vitro model of amyotrophic lateral sclerosis. PLoS One. 2017; 28(12):e0176462 .
  • Wolozin B, Ivanov P. Stress granules and neurodegeneration. Nat Rev Neurosci. 2019;20(11):649–666.
  • Jain S, Wheeler JR, and Walters RW, et al. ATPase-modulated stress granules contain a diverse proteome and substructure. Cell . 2016;164(3):487–498.
  • Fernandes N, Nero L, Lyons SM, et al. Stress granule assembly can facilitate but is not required for TDP‐43 cytoplasmic aggregation. Biomolecules. 2020;10(10):1367.
  • Marmor-Kollet H, Siany A, Kedersha N, et al. Spatiotemporal Proteomic Analysis of Stress Granule Disassembly Using APEX Reveals Regulation by SUMOylation and Links to ALS Pathogenesis. Mol Cell. 2020;80(5):876–891.e6.
  • Vu L, Ghosh A, Tran C, et al. Defining the Caprin-1 Interactome in Unstressed and Stressed Conditions. J Proteome Res. 2021;20(6):3165–3178.
  • Turner MR. Progress and new frontiers in biomarkers for amyotrophic lateral sclerosis. Biomark Med. 2018;12(7):693–696.
  • Poesen K, and Van Damme P. Diagnostic and prognostic performance of neurofilaments in ALS. Front. Neurol. 2019; 9 1167 .
  • Figlewicz DA, Krizus A, Martinoli MG, et al. Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum Mol Genet. 1994;3(10):1757–1761.
  • Steinacker P, Feneberg E, and Weishaupt J, et al. Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients. J Neurol Neurosurg Psychiatry . 2016;87(1):12–20.
  • Feneberg E, Oeckl P, and Steinacker P, et al. Multicenter evaluation of neurofilaments in early symptom onset amyotrophic lateral sclerosis. Neurology . 2018;90(1):e22–e30.
  • Lu CH, Macdonald-Wallis C, and Gray E, et al. Neurofilament light chain: a prognostic biomarker in amyotrophic lateral sclerosis. Neurology . 2015;84(22):2247–2257.
  • Ganesalingam J, An J, Shaw CE, et al. Combination of neurofilament heavy chain and complement C3 as CSF biomarkers for ALS. J Neurochem. 2011;117(3):528–537.
  • Turner MR, and Gray E. Are neurofilaments heading for the ALS clinic? J Neurol Neurosurg Psychiatry. . 2016;87(1):3–4.
  • Lewczuk P, Riederer P, and O’Bryant SE, et al. Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: an update of the consensus of the task force on biological markers in psychiatry of the world federation of societies of biological psychiatry. World J Biol Psychiatry . 2018;19(4):244–328.
  • Fairfoul G, McGuire LI, Pal S, et al. Alpha-synuclein RT-Qu IC in the CSF of patients with alpha-synucleinopathies. Ann Clin Transl Neurol. 2016;3(10):812–818.
  • Atarashi R, Sano K, Satoh K, et al. Real-time quaking-induced conversion: a highly sensitive assay for prion detection. Prion. 2011;5(3):150–153.
  • Paganoni S, Cudkowicz M, and Berry JD. Outcome measures in amyotrophic lateral sclerosis clinical trials Clin Investig (Lond) . . 2014;4(7):605–618
  • Van Eijk RPA, Westeneng HJ, Nikolakopoulos S, et al. Refining eligibility criteria for amyotrophic lateral sclerosis clinical trials. Neurology. 2019;92(5):e451–e460.
  • Turner MR, and Benatar M. Ensuring continued progress in biomarkers for amyotrophic lateral sclerosis. Muscle Nerve. . 2015;51(1):14–18.
  • Winer L, Srinivasan D, and Chun S, et al. SOD1 in cerebral spinal fluid as a pharmacodynamic marker for antisense oligonucleotide therapy. JAMA Neurol . 2013;70(2):201–207.
  • Gendron TF, Chew J, and Jn S, et al. Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. Sci Transl Med. 2017; 9(38: eaai7866
  • Shepheard SR, Wuu J, Cardoso M, et al. Urinary p75 ECD. Neurology. 2017;88(12):1137–1143.
  • Gendron TF, Daughrity LM, Heckman MG, et al. Phosphorylated neurofilament heavy chain: a biomarker of survival for C9ORF 72 -associated amyotrophic lateral sclerosis. Ann Neurol. 2017;82(1):139–146.
  • Benatar M, Zhang L, Wang L, et al. Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS. Neurology. 2020;95(1):e59–e69.
  • Miller T, Cudkowicz M, Shaw PJ, et al. Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2020;383(2):109–119.
  • Milligan C, Atassi N, Babu S, et al. Tocilizumab is safe and tolerable and reduces C-reactive protein concentrations in the plasma and cerebrospinal fluid of ALS patients. Muscle Nerve. 2021;64(3):309–320.
  • Guldbrandsen A, Farag Y, Kroksveen AC, et al. CSF-PR 2.0: an interactive literature guide to quantitative cerebrospinal fluid mass spectrometry data from neurodegenerative disorders. Mol Cell Proteomics. 2017;16(2):300–309.
  • Dayon L, Cominetti O, Wojcik J, et al. Proteomes of Paired Human Cerebrospinal Fluid and Plasma: relation to Blood-Brain Barrier Permeability in Older Adults. J Proteome Res. 2019;18(3):1162–1174.
  • Barschke P, Oeckl P, and Steinacker P, et al. Proteomic studies in the discovery of cerebrospinal fluid biomarkers for amyotrophic lateral sclerosis. Expert Rev Proteomics . 2017;14(9):769–777.
  • Ranganathan S, Nicholl GC, and Henry S, et al. Comparative proteomic profiling of cerebrospinal fluid between living and post mortem ALS and control subjects. Amyotroph Lateral Scler . 2007;8(6):373–379.
  • Brettschneider J, Lehmensiek V, Mogel H, et al. Proteome analysis reveals candidate markers of disease progression in amyotrophic lateral sclerosis (ALS). Neurosci Lett. 2010;468(1):23–27.
  • Collins M, Riascos D, Kovalik T, et al. The RNA-binding motif 45 (RBM45) protein accumulates in inclusion bodies in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) patients. Acta Neuropathol. 2012;124(5):717–732.
  • Bereman MS, Beri J, and Enders JR, et al. Machine Learning Reveals Protein Signatures in CSF and Plasma Fluids of Clinical Value for ALS. Sci Rep. 2018;8(1).
  • Zhu S, Wuolikainen A, Wu J, et al. Targeted Multiple Reaction Monitoring Analysis of CSF Identifies UCHL1 and GPNMB as Candidate Biomarkers for ALS. J Mol Neurosci. 2019;69(4):643–657.
  • Mellinger AL, Griffith EH, Bereman MS. Peptide variability and signatures associated with disease progression in CSF collected longitudinally from ALS patients. Anal Bioanal Chem. 2020;412(22):5465–5475.
  • Palma AS, De Carvalho M, Grammel N, et al. Proteomic analysis of plasma from Portuguese patients with familial amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2008;9(6):339–349.
  • Häggmark A, Mikus M, Mohsenchian A, et al. Plasma profiling reveals three proteins associated to amyotrophic lateral sclerosis. Ann Clin Transl Neurol. 2014;1(8):544–553.
  • Ramstrom M, Ivonin I, and Johansson A, et al. Cerebrospinal fluid protein patterns in neurodegenerative disease revealed by liquid chromatography-Fourier transform ion cyclotron resonance mass spectrometry. Proteomics . 2004;4(12)::4010–4018.
  • Collins MA, An J, and Hood BL, et al. Label-Free LC-MS/MS Proteomic Analysis of Cerebrospinal Fluid Identifies Protein/Pathway Alterations and Candidate Biomarkers for Amyotrophic Lateral Sclerosis. J Proteome Res . 2015;14(11):4486–4501.
  • Ranganathan S, Williams E, and Ganchev P, et al. Proteomic profiling of cerebrospinal fluid identifies biomarkers for amyotrophic lateral sclerosis. J Neurochem . 2005;95(5):1461–1471.
  • Pasinetti GM, Ungar LH, and Lange DJ, et al. Identification of potential CSF biomarkers in ALS. Neurology . 2006;66(8):1218–1222.
  • Ryberg H, An J, and Darko S, et al. Discovery and verification of amyotrophic lateral sclerosis biomarkers by proteomics. Muscle Nerve . 2010;42(1):104–111.
  • Sako W, Ishimoto S. Can cystatin C in cerebrospinal fluid be a biomarker for amyotrophic lateral sclerosis? A lesson from previous studies. Neurol Clin Neurosci. 2014;2(3):72–75.
  • Tsuji-Akimoto S, Yabe I, Niino M, et al. Cystatin C in cerebrospinal fluid as a biomarker of ALS. Neurosci Lett. 2009;452(1):52–55.
  • Thompson AG, Gray E, Bampton A, et al. CSF chitinase proteins in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2019;90(11):1215–1220.
  • Lunetta C, Lizio A, Maestri E, et al. Serum C-reactive protein as a prognostic biomarker in amyotrophic lateral sclerosis. JAMA Neurol. 2017;74(6):660.
  • Beers DR, Zhao W, and Neal DW, et al. Elevated acute phase proteins reflect peripheral inflammation and disease severity in patients with amyotrophic lateral sclerosis. Sci Rep. 2020;10(1).
  • Brettschneider J, Mogel H, and Lehmensiek V, et al. Proteome analysis of cerebrospinal fluid in amyotrophic lateral sclerosis (ALS). Neurochem Res . 2008;33(11):2358–2363.
  • Mendonca DM, Pizzati L, and Mostacada K, et al. Neuroproteomics: an insight into ALS. Neurol Res . 2012;34(10):937–943.
  • Wormser U, Mandrioli J, and Vinceti M, et al. Reduced levels of alpha-1-antitrypsin in cerebrospinal fluid of amyotrophic lateral sclerosis patients: a novel approach for a potential treatment. J Neuroinflammation. 2016;13(1).
  • Von Neuhoff N, Oumeraci T, Wolf T, et al. Monitoring CSF proteome alterations in amyotrophic lateral sclerosis: obstacles and perspectives in translating a novel marker panel to the clinic. PLoS One [Internet]. 2012;7(9):e44401.
  • Chen Y, Liu XH, Wu JJ, et al. Proteomic analysis of cerebrospinal fluid in amyotrophic lateral sclerosis. Exp Ther Med [Internet]. 2016;11(6):2095–2106.
  • Varghese AM, Sharma A, Mishra P, et al. Chitotriosidase - a putative biomarker for sporadic amyotrophic lateral sclerosis. Clin Proteomics [Internet]. 2013;10(1):19.
  • Oeckl P, Weydt P, Steinacker P, et al. Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase. J Neurol Neurosurg Psychiatry. 2019;90(1):4–10.
  • Thompson AG, Gray E, Thézénas ML, et al. Cerebrospinal fluid macrophage biomarkers in amyotrophic lateral sclerosis. Ann Neurol. 2018;83(2):258–268.
  • Gray E, Thompson AG, Wuu J, et al. CSF chitinases before and after symptom onset in amyotrophic lateral sclerosis. Ann Clin Transl Neurol. 2020;7(8):1296–1306.
  • Steinacker P, Verde F, Fang L, et al. Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression. J Neurol Neurosurg Psychiatry [Internet]. 2018;89(3):239–247.
  • Gille B, De Schaepdryver M, and Dedeene L, et al. Inflammatory markers in cerebrospinal fluid: independent prognostic biomarkers in amyotrophic lateral sclerosis? J Neurol Neurosurg Psychiatry. 2019;1338–46. .
  • Vu L, An J, Kovalik T, et al. Cross-sectional and longitudinal measures of chitinase proteins in amyotrophic lateral sclerosis and expression of CHI3L1 in activated astrocytes. J Neurol Neurosurg Psychiatry. 2020;91(4):350–358.
  • Varghese AM, Ghosh M, and Bhagat SK, et al. Chitotriosidase, a biomarker of amyotrophic lateral sclerosis, accentuates neurodegeneration in spinal motor neurons through neuroinflammation. J Neuroinflammation. 2020;17(1).
  • Gaur N, Perner C, and Witte OW, et al. The Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis: signals From the CNS and Beyond. Front Neurol. 2020;11.
  • Barschke P, Oeckl P, Steinacker P, et al. Different CSF protein profiles in amyotrophic lateral sclerosis and frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. J Neurol Neurosurg Psychiatry. 2020;91(5):503–511.
  • Thompson AG, Gray E, and Heman-Ackah SM, et al. Extracellular vesicles in neurodegenerative disease - pathogenesis to biomarkers. Nat Rev Neurol . 2016;12(6):346–357.
  • Aoki Y, Manzano R, Lee Y, et al. C9orf72 and RAB7L1 regulate vesicle trafficking in amyotrophic lateral sclerosis and frontotemporal dementia. Brain. 2017;140(4):887–897.
  • Thompson AG, Gray E, Mager I, et al. UFLC-Derived CSF Extracellular Vesicle Origin and Proteome. Proteomics. 2018;18:1800257.
  • Feneberg E, Steinacker P, and Lehnert S, et al. Limited role of free TDP-43 as a diagnostic tool in neurodegenerative diseases. Amyotroph Lateral Scler Front Degener . 2014;15:351–356. (
  • Thompson AG, Gray E, and Mäger I, et al. CSF extracellular vesicle proteomics demonstrates altered protein homeostasis in amyotrophic lateral sclerosis. Clin Proteomics. 2020;17(1).
  • Hayashi N, Doi H, Kurata Y, et al. Proteomic analysis of exosome-enriched fractions derived from cerebrospinal fluid of amyotrophic lateral sclerosis patients. Neurosci Res. 2019;160:43–49.
  • Mustapic M, Eitan E, and Werner JK, et al. Plasma extracellular vesicles enriched for neuronal origin: a potential window into brain pathologic processes. Front Neurosci. 2017;11.
  • Goetzl EJ, Boxer A, Schwartz JB, et al. Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology. 2015;85(1):40–47.
  • Jiang C, Hopfner F, Hopfner F, et al. Serum neuronal exosomes predict and differentiate Parkinson’s disease from atypical parkinsonism. J Neurol Neurosurg Psychiatry. 2020;91(7):720–729.
  • Norman M, Ter-Ovanesyan D, Trieu W, et al. L1CAM is not associated with extracellular vesicles in human cerebrospinal fluid or plasma. Nat Methods. 2021;18(6):631–634.
  • Benatar M, Wuu J, Andersen PM, et al. Neurofilament light: a candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion. Ann Neurol. 2018;84(1):130–139.
  • Vucic S, Nicholson GA, and Kiernan MC. Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain. 2008;131(6):1540–1550.
  • 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):152–158.
  • Benatar M, Wuu J. Presymptomatic studies in ALS: rationale, challenges, and approach. Neurology. 2012;79(16):1732–1739.
  • Leoni E, Bremang M, and Mitra V, et al. Combined Tissue-Fluid Proteomics to Unravel Phenotypic Variability in Amyotrophic Lateral Sclerosis. Sci Rep. 2019;9(1).
  • Zubiri I, Lombardi V, and Bremang M, et al. Tissue-enhanced plasma proteomic analysis for disease stratification in amyotrophic lateral sclerosis. Mol Neurodegener. 2018;13(1).
  • Conraux L, Pech C, Guerraoui H, et al. Plasma peptide biomarker discovery for amyotrophic lateral sclerosis by MALDI-TOF mass spectrometry profiling. PLoS One. 2013;8(11):e79733.
  • Xu Z, Lee A, Nouwens A, et al. Mass spectrometry analysis of plasma from amyotrophic lateral sclerosis and control subjects. Amyotroph Lateral Scler Front Degener. 2018;19(5–6):362–376.
  • Katzeff JS, Bright F, and Lo K, et al. Altered serum protein levels in frontotemporal dementia and amyotrophic lateral sclerosis indicate calcium and immunity dysregulation. Sci Rep. 2020;10(1) .
  • Nardo G, Pozzi S, Mantovani S, et al. Nitroproteomics of peripheral blood mononuclear cells from patients and a rat model of ALS. Antioxid Redox Signal. 2009;11(7):1559–1567.
  • Nardo G, Pozzi S, Pignataro M, et al. Amyotrophic lateral sclerosis multiprotein biomarkers in peripheral blood mononuclear cells. PLoS One. 2011;6(10):e25545.
  • Thompson AG, Gray E, and Charles PD, et al. Network Analysis of the CSF Proteome Characterizes Convergent Pathways of Cellular Dysfunction in ALS. Front Neurosci. 2021;15.
  • Higginbotham L, Ping L, Dammer EB, et al. Integrated proteomics reveals brain-based cerebrospinal fluid biomarkers in asymptomatic and symptomatic Alzheimer’s disease. Sci Adv. 2020;6(43):eaaz9360.
  • Aslam B, Basit M, Nisar MA, et al. Proteomics: technologies and their applications. J Chromatogr Sci. 2017;55(2):182–196.
  • Van Damme P, Robberecht W, Van Den Bosch L. Modelling amyotrophic lateral sclerosis: progress and possibilities. DMM Dis Model Mech. 2017;10(5):537–549.
  • Wong CO, Venkatachalam K. Motor neurons from ALS patients with mutations in C9ORF72 and SOD1 exhibit distinct transcriptional landscapes. Hum Mol Genet. 2019;28(16):2799–2810.
  • Morello G, Salomone S, and D’Agata V, et al. From Multi-Omics Approaches to Precision Medicine in Amyotrophic Lateral Sclerosis. Front Neurosci. 2020;14.
  • Niehaus M, Soltwisch J, Belov ME, et al. Transmission-mode MALDI-2 mass spectrometry imaging of cells and tissues at subcellular resolution. Nat Methods. 2019;16(9):925–931.
  • Acquadro E, Caron I, Tortarolo M, et al. Human SOD1-G93A specific distribution evidenced in murine brain of a transgenic model for amyotrophic lateral sclerosis by MALDI imaging mass spectrometry. J Proteome Res. 2014;13(4):1800–1809.
  • Xu BJ. Combining laser capture microdissection and proteomics: methodologies and clinical applications. Proteomics - Clin Appl. 2010;4(2):116–123.
  • Schoof EM, Furtwängler B, and Üresin N, et al. Quantitative single-cell proteomics as a tool to characterize cellular hierarchies. Nat Commun. 2021;12(1).
  • Gut G, Herrmann MD, and Pelkmans L. Multiplexed protein maps link subcellular organization to cellular states. Science. 2018;361(6401).
  • Li KW, Gonzalez-Lozano MA, and Koopmans F, et al. Recent Developments in Data Independent Acquisition (DIA) Mass Spectrometry: application of Quantitative Analysis of the Brain Proteome. Front Mol Neurosci. 2020;13.
  • Halvey P, Farutin V, and Koppes L, et al. Variable blood processing procedures contribute to plasma proteomic variability. Clin Proteomics. 2021;18(1).
  • Robelin L, Gonzalez De Aguilar JL. Blood biomarkers for amyotrophic lateral sclerosis: myth or reality? BioMed Res Int. 2014;2014:1–11.
  • Carlyle BC, Trombetta BA, Arnold SE. Proteomic approaches for the discovery of biofluid biomarkers of neurodegenerative dementias. Proteomes. 2018;6(3):32.