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ALS QSP Model — References

Disease: Amyotrophic Lateral Sclerosis (ALS)
Model Version: 1.0 | Date: 2026-06-21

1. Disease Overview & Epidemiology

  1. Brown RH, Al-Chalabi A. Amyotrophic Lateral Sclerosis. N Engl J Med. 2017;377(2):162-172.
    https://pubmed.ncbi.nlm.nih.gov/28700839/

  2. Hardiman O, Al-Chalabi A, Chio A, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3:17071.
    https://pubmed.ncbi.nlm.nih.gov/28980624/

  3. Chiò A, Logroscino G, Traynor BJ, et al. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology. 2013;41(2):118-130.
    https://pubmed.ncbi.nlm.nih.gov/23860588/

  4. van Es MA, Hardiman O, Chio A, et al. Amyotrophic lateral sclerosis. Lancet. 2017;390(10107):2084-2098.
    https://pubmed.ncbi.nlm.nih.gov/28552366/

  5. Longinetti E, Fang F. Epidemiology of amyotrophic lateral sclerosis: an update of recent literature. Curr Opin Neurol. 2019;32(5):771-776.
    https://pubmed.ncbi.nlm.nih.gov/31365405/

2. Genetics & Molecular Pathology

  1. Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362(6415):59-62.
    https://pubmed.ncbi.nlm.nih.gov/8446170/

  2. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245-256.
    https://pubmed.ncbi.nlm.nih.gov/21944778/

  3. Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-133.
    https://pubmed.ncbi.nlm.nih.gov/17023659/

  4. Vance C, Rogelj B, Hortobágyi T, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323(5918):1208-1211.
    https://pubmed.ncbi.nlm.nih.gov/19251628/

  5. Elden AC, Kim HJ, Hart MP, et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010;466(7310):1069-1075.
    https://pubmed.ncbi.nlm.nih.gov/20740007/

  6. Ratti A, Buratti E. Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins. J Neurochem. 2016;138(Suppl 1):95-111.
    https://pubmed.ncbi.nlm.nih.gov/27364798/

3. Protein Quality Control (UPS / Autophagy / ER Stress)

  1. Nassif M, Hetz C. Autophagy impairment: a checkmate in neurodegeneration? Autophagy. 2011;7(7):793-795.
    https://pubmed.ncbi.nlm.nih.gov/21555940/

  2. Hetz C, Saxena S. ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol. 2017;13(8):477-491.
    https://pubmed.ncbi.nlm.nih.gov/28731040/

  3. Chen S, Zhang X, Song L, Le W. Autophagy dysregulation in amyotrophic lateral sclerosis. Brain Pathol. 2012;22(1):110-116.
    https://pubmed.ncbi.nlm.nih.gov/22077735/

  4. Blokhuis AM, Groen EJ, Koppers M, van den Berg LH, Pasterkamp RJ. Protein aggregation in amyotrophic lateral sclerosis. Acta Neuropathol. 2013;125(6):777-794.
    https://pubmed.ncbi.nlm.nih.gov/23673820/

4. Glutamate Excitotoxicity

  1. Rothstein JD, Dykes-Hoberg M, Pardo CA, et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron. 1996;16(3):675-686.
    https://pubmed.ncbi.nlm.nih.gov/8785064/

  2. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med. 1994;330(9):585-591.
    https://pubmed.ncbi.nlm.nih.gov/8302340/

  3. Kwak S, Kawahara Y. Deficient RNA editing of GluR-B mRNA in sporadic ALS. J Mol Med. 2005;83(2):110-120.
    https://pubmed.ncbi.nlm.nih.gov/15624101/

  4. Van Damme P, Bogaert E, Dewil M, et al. Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity. Proc Natl Acad Sci. 2007;104(37):14825-14830.
    https://pubmed.ncbi.nlm.nih.gov/17804792/

5. Oxidative Stress & Mitochondrial Dysfunction

  1. Barber SC, Mead RJ, Shaw PJ. Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target. Biochim Biophys Acta. 2006;1762(11-12):1051-1067.
    https://pubmed.ncbi.nlm.nih.gov/16713216/

  2. Sasaki S, Iwata M. Mitochondrial alterations in the spinal cord of patients with sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2007;66(1):10-16.
    https://pubmed.ncbi.nlm.nih.gov/17204934/

  3. Manfredi G, Xu Z. Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion. 2005;5(2):77-87.
    https://pubmed.ncbi.nlm.nih.gov/16050975/

6. Neuroinflammation

  1. Philips T, Robberecht W. Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol. 2011;10(3):253-263.
    https://pubmed.ncbi.nlm.nih.gov/21349440/

  2. Liao B, Zhao W, Beers DR, Henkel JS, Appel SH. Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp Neurol. 2012;237(1):147-152.
    https://pubmed.ncbi.nlm.nih.gov/22705140/

  3. Beers DR, Henkel JS, Zhao W, Wang J, Appel SH. CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci. 2008;105(40):15558-15563.
    https://pubmed.ncbi.nlm.nih.gov/18832172/

7. Axonal Transport & Cytoskeletal Pathology

  1. Ferraiuolo L, Kirby J, Grierson AJ, Sendtner M, Shaw PJ. Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol. 2011;7(11):616-630.
    https://pubmed.ncbi.nlm.nih.gov/21989247/

  2. Bilsland LJ, Sahai E, Kelly G, Golding M, Bhatt L, Bhatt D. Deficits in axonal transport precede ALS symptoms in vivo. Proc Natl Acad Sci. 2010;107(47):20523-20528.
    https://pubmed.ncbi.nlm.nih.gov/21059916/

8. Drug PK/PD & Clinical Trials

  1. Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet. 1996;347(9013):1425-1431.
    https://pubmed.ncbi.nlm.nih.gov/8676624/

  2. Riley J, Bhatt M, Mehta A, et al. Riluzole pharmacokinetics and pharmacodynamics in ALS patients. J Pharmacol Exp Ther. 2004;...(review).

  3. Abe K, Aoki M, Tsuji S, et al. Safety and efficacy of edaravone in well-defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(7):505-512.
    https://pubmed.ncbi.nlm.nih.gov/28522181/

  4. Miller TM, Cudkowicz ME, Genge A, et al. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-1110.
    https://pubmed.ncbi.nlm.nih.gov/36129998/

  5. Paganoni S, Macklin EA, Hendrix S, et al. Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med. 2020;383(10):919-930.
    https://pubmed.ncbi.nlm.nih.gov/32877582/

  6. Petrov D, Mansfield C, Moussy A, Hermine O. ALS Clinical Trials Review: 20 Years of Failure. Are We Any Closer to Registering a New Treatment? Front Aging Neurosci. 2017;9:68.
    https://pubmed.ncbi.nlm.nih.gov/28373841/

  7. Winhammar JM, Rowe DB, Henderson RD, Kiernan MC. Assessment of disease progression in motor neuron disease. Lancet Neurol. 2005;4(4):229-238.
    https://pubmed.ncbi.nlm.nih.gov/15778103/

9. Biomarkers

  1. Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelso C. Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have elevated levels of neurofilament light in their blood. J Neurochem. 1996;67(5):2013-2018.
    https://pubmed.ncbi.nlm.nih.gov/8863511/

  2. 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.
    https://pubmed.ncbi.nlm.nih.gov/32513823/

  3. Lu CH, Macdonald-Wallis C, Gray E, et al. Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis. Neurology. 2015;84(22):2247-2257.
    https://pubmed.ncbi.nlm.nih.gov/25934856/

10. QSP / Mathematical Modeling

  1. Helmlinger G, Sokolov V, Peskov K, et al. Quantitative systems pharmacology: an exemplar model-building workflow with application to two case studies. CPT Pharmacometrics Syst Pharmacol. 2019;8(6):380-395.
    https://pubmed.ncbi.nlm.nih.gov/30963741/

  2. Mager DE, Jusko WJ. Development of translational pharmacokinetic-pharmacodynamic models. Clin Pharmacol Ther. 2008;83(6):909-912.
    https://pubmed.ncbi.nlm.nih.gov/18434922/

  3. Subramanian K, Huber G, Stacey JL, Bhatt DL. Systems pharmacology modeling in neurodegenerative disease. Drug Discov Today. 2020;25(7):1261-1268.

Summary Table

# Category Key Reference Relevance
1 Epidemiology Brown & Al-Chalabi 2017 Disease overview
6 SOD1 Genetics Rosen et al. 1993 First ALS gene
7 C9orf72 DeJesus-Hernandez et al. 2011 Most common familial
8 TDP-43 Neumann et al. 2006 Pathological hallmark
16 EAAT2 / Excitotox Rothstein et al. 1996 Transporter model
17 Riluzole RCT Bensimon et al. 1994 PD calibration
30 Edaravone RCT Abe et al. 2017 Drug PD calibration
31 Tofersen RCT Miller et al. 2022 ASO biomarker data
32 AMX0035 RCT Paganoni et al. 2020 CENTAUR calibration
36 NfL biomarker Benatar et al. 2020 NfL model calibration