Decoding Amyotrophic Lateral Sclerosis: A Systems Biology Approach
Jay Lombard, DO
Root Cause Medicine Practice, Valley Cottage, NY, USA
Michael Hamper, MBs
Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA
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Keywords

ALS; Infectious; Autophagy; TBI; Neurodegeneration
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Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of upper and lower motor neurons in the motor cortex, brain stem, and the anterior horn of the spinal cord. The majority of ALS cases are classified as sporadic (sALS). There is a growing concern regarding the increased incidence in the number of sporadic ALS cases across the world, projected to increase by almost 70% in the next two decades. The etiology of sporadic ALS is currently unknown; however, epidemiological studies point to possible exposure of environmental triggers, including trauma and infections as risk factors for the development of motor neuron pathology. On a pathological basis, protein misfolding with the accumulation of cytoplasmic inclusions of TDP-43 are regarded as the hallmark feature of ALS pathogenesis. The cellular mechanisms that lead to protein aggregation are not completely understood, but appear to involve defects in autophagy, an intracellular autodigestive process that degrades misfolded proteins like TDP-43. This review will be split into two portions: (1) discuss the evidence regarding how various environmental risk factors, such as infections agents and physical trauma, can lead to neuropathological changes by disrupting autophagy in ALS; (2) discuss potential treatment options in the management of each environmental factor previously discussed.

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References

1. Valbuena GN, Cantoni L, Tortarolo M, et al. Spinal cord metabolic signatures in models of fast- and slowprogressing SOD1G93A amyotrophic lateral sclerosis. Front Neurosci. 2019;13:1276. https://doi.org/10.3389/fnins.2019.01276.
2. Chiò A, Calvo A, Moglia C, et al. Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study. J Neurol Neurosurg Psychiatry. 2011;82(7):740–6. https://doi.org/10.1136/jnnp.2010.235952.
3. Pupillo E, Messina P, Logroscino G, et al. Long-term survival in amyotrophic lateral sclerosis: a populationbased study. Ann Neurol. 2014;75(2):287–97. https://doi.org/10.1002/ana.24096.
4. Fournier C, Glass JD. Modeling the course of amyotrophic lateral sclerosis [published correction appears in Nat Biotechnol. 2015;33(5):563]. Nat Biotechnol. 2015;33(1):45–7. https://doi.org/10.1038/nbt.3118.
5. Régal L, Vanopdenbosch L, Tilkin P, et al. The G93C mutation in superoxide dismutase 1: clinicopathologic phenotype and prognosis [published correction appears in Arch Neurol. 2006;63(7):963]. Arch Neurol. 2006;63(2):262–7. https://doi.org/10.1001/archneur.63.2.262.
6. Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130–3. https://doi.org/10.1126/science.1134108.
7. Johnson BS, Snead D, Lee JJ, et al. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosislinked mutations accelerate aggregation and increase toxicity [published correction appears in J Biol Chem. 2009;284(37):25459]. J Biol Chem. 2009;284(30):20329– 39. https://doi.org/10.1074/jbc.M109.010264.
8. Gonzalez D, Contreras O, Rebolledo DL, et al. ALS skeletal muscle shows enhanced TGF-ß signaling, fibrosis and induction of fibro/adipogenic progenitor markers. PLoS One. 2017;12(5):e0177649. https://doi.org/10.1371/journal.pone.0177649.
9. Ou SH, Wu F, Harrich D, et al. Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol. 1995;69(6):3584–96. https://doi.org/10.1128/JVI.69.6.3584-3596.1995.
10. Alfahad T, Nath A. Retroviruses and amyotrophic lateral sclerosis. Antiviral Res. 2013;99(2):180–7. https://doi.org/10.1016/j.antiviral.2013.05.006.
11. Howe MD, Furr JW, Munshi Y, et al. Transforming growth factor-ß promotes basement membrane fibrosis, alters perivascular cerebrospinal fluid distribution, and worsens neurological recovery in the aged brain after stroke. Geroscience. 2019;41(5):543–59. https://doi.org/10.1007/s11357-019-00118-7.
12. Luo L. Rho GTPases in neuronal morphogenesis. Nat Rev Neurosci. 2000;1(3):173–80. https://doi.org/10.1038/35044547.
13. Stankiewicz TR, Pena C, Bouchard RJ, Linseman DA. Dysregulation of Rac or Rho elicits death of motor neurons and activation of these GTPases is altered in the G93A mutant hSOD1 mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2020;136:104743. https://doi.org/10.1016/j.nbd.2020.104743.
14. Leoni E, Bremang M, Mitra V, et al. Combined tissuefluid proteomics to unravel phenotypic variability in amyotrophic lateral Sclerosis. Sci Rep. 2019;9(1):4478. https://doi.org/10.1038/s41598-019-40632-4.
15. Iguchi Y, Katsuno M, Niwa JI, et al. TDP-43 depletion induces neuronal cell damage through dysregulation of Rho family GTPases. J Biol Chem. 2009;284(33): 22059–66. https://doi.org/10.1074/jbc.M109.012195.
16. Linseman DA, Loucks FA. Diverse roles of Rho family GTPases in neuronal development, survival, and death. Front Biosci. 2008;13:657–76. https://doi.org/10.2741/2710.
17. Stankiewicz TR, Linseman DA. Rho family GTPases: key players in neuronal development, neuronal survival, and neurodegeneration. Front Cell Neurosci. 2014;8:314. https://doi.org/10.3389/fncel.2014.00314.
18. Popoff MR. Bacterial factors exploit eukaryotic Rho GTPase signaling cascades to promote invasion and proliferation within their host. Small GTPases. 2014;5. https://doi.org/10.4161/sgtp.28209.
19. Dufies O, Doye A, Courjon J, et al. Escherichia coli Rho GTPase-activating toxin CNF1 mediates NLRP3 inflammasome activation via p21-activated kinases-1/2 during bacteraemia in mice. Nat Microbiol. 2021;6(3):401–12. https://doi.org/10.1038/s41564-020-00832-5.
20. Lucera MB, Fleissner Z, Tabler CO, et al. HIV signaling through CD4 and CCR5 activates Rho family GTPases that are required for optimal infection of primary CD4 + T cells. Retrovirology. 2017;14(1):4. https://doi.org/10.1186/s12977-017-0328-7.
21. Drewry LL, Sibley LD. The hitchhiker’s guide to parasite dissemination. Cell Microbiol. 2019;21(11):e13070. https://doi.org/10.1111/cmi.13070.
22. Latgé JP, Chamilos G. Aspergillus fumigatus and aspergillosis in 2019. Clin Microbiol Rev. 2019;33(1):e00140–18. https://doi.org/10.1128/CMR.00140-18.
23. Lahiani A, Yavin E, Lazarovici P. The molecular basis of toxins’ interactions with intracellular signaling via discrete portals. Toxins (Basel). 2017;9(3):107. https://doi.org/10.3390/toxins9030107.
24. Kogan TV, Jadoun J, Mittelman L, et al. Involvement of secreted Aspergillus fumigatus proteases in disruption of the actin fiber cytoskeleton and loss of focal adhesion sites in infected A549 lung pneumocytes. J Infect Dis. 2004;189(11):1965–73. https://doi.org/10.1086/420850.
25. French PW, Ludowyke R, Guillemin GJ. Fungal neurotoxins and sporadic amyotrophic lateral sclerosis. Neurotox Res. 2019;35(4):969–80. https://doi.org/10.1007/s12640-018-9980-5.
26. 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):546–58. https://doi.org/10.7150/ijbs.11084.
27. Levine B, Deretic V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol. 2007;7(10):767–77. https://doi.org/10.1038/nri2161.
28. Bonam SR, Wang F, Muller S. Lysosomes as a therapeutic target. Nat Rev Drug Discov. 2019;18(12):923–48. https://doi.org/10.1038/s41573-019-0036-1.
29. Huang J, Brumell JH. Bacteria-autophagy interplay: a battle for survival. Nat Rev Microbiol. 2014;12(2):101114. https://doi.org/10.1038/nrmicro3160.
30. Abdoli A, Alirezaei M, Mehrbod P, Forouzanfar F. Autophagy: The multi-purpose bridge in viral infections and host cells. Rev Med Virol. 2018;28(4):e1973. https://doi.org/10.1002/rmv.1973.
31. Perez-Nadales E, Nogueira MF, Baldin C, et al. Fungal model systems and the elucidation of pathogenicity determinants. Fungal Genet Biol. 2014;70(100):42–67. https://doi.org/10.1016/j.fgb.2014.06.011.
32. Sentürk M, Mao D, Bellen HJ. Loss of proteins associated with amyotrophic lateral sclerosis affects lysosomal acidification via different routes. Autophagy. 2019;15(8):1467–9. https://doi.org/10.1080/15548627.2019.1609863.
33. Wang L, Li C, Chen X, et al. Abnormal serum iron-status indicator changes in amyotrophic lateral sclerosis (ALS) patients: a meta-analysis. Front Neurol. 2020;11:380. https://doi.org/10.3389/fneur.2020.00380.
34. Larson JA, Howie HL, So M. Neisseria meningitidis accelerates ferritin degradation in host epithelial cells to yield an essential iron source. Mol Microbiol. 2004;53(3):807–20. https://doi.org/10.1111/j.1365- 2958.2004.04169.x.
35. Sousa Gerós A, Simmons A, Drakesmith H, et al. The battle for iron in enteric infections. Immunology. 2020;161(3):186–99. https://doi.org/10.1111/imm.13236.
36. Houamel D, Ducrot N, Lefebvre T, et al. Hepcidin as a major component of renal antibacterial defenses against uropathogenic Escherichia coli. J Am Soc Nephrol. 2016;27(3):835–46. https://doi.org/10.1681/ASN.2014101035.
37. MacKenzie EL, Iwasaki K, Tsuji Y. Intracellular iron transport and storage: from molecular mechanisms to health implications. Antioxid Redox Signal. 2008;10(6):997–1030. https://doi.org/10.1089/ars.2007.1893.
38. Weber RA, Yen FS, Nicholson SPV, et al. Maintaining iron homeostasis is the key role of lysosomal acidity for cell proliferation. Mol Cell. 2020;77(3):645–55.e7. https://doi.org/10.1016/j.molcel.2020.01.003.
39. Colacurcio DJ, Nixon RA. Disorders of lysosomal acidification–the emerging role of v-ATPase in aging and neurodegenerative disease. Ageing Res Rev. 2016;32:75– 88. https://doi.org/10.1016/j.arr.2016.05.004.
40. Forgac M. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat Rev Mol Cell Biol. 2007;8(11):917–29. https://doi.org/10.1038/nrm2272.
41. Saroussi S, Nelson N. The little we know on the structure and machinery of V-ATPase. J Exp Biol. 2009;212(Pt 11):1604–10. https://doi.org/10.1242/jeb.025866.
42. Blasco H, Vourc’h P, Nadjar Y, et al. Association between divalent metal transport 1 encoding gene (SLC11A2) and disease duration in amyotrophic lateral sclerosis. J Neurol Sci. 2011;303(1–2):124–7. https://doi.org/10.1016/j.jns.2010.12.018.
43. Mackenzie B, Hediger MA. SLC11 family of H + -coupled metal-ion transporters NRAMP1 and DMT1. Pflugers Arch. 2004;447(5):571–9. https://doi.org/10.1007/s00424-003-1141-9.
44. Foka P, Dimitriadis A, Karamichali E, et al. HCVinduced immunometabolic crosstalk in a triple-cell co-culture model capable of simulating systemic iron homeostasis. Cells. 2021;10(9);2251. https://doi.org/10.3390/cells10092251.
45. Jiang S, Guo S, Li H, et al. Identification and functional verification of microRNA-16 family targeting intestinal divalent metal transporter 1 (DMT1). Front Physiol. 2019;10:819. https://doi.org/10.3389/fphys.2019.00819.
46. Béland LC, Markovinovic A, Jakovac H, et al. Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses. Brain Commun. 2020;2(2):fcaa124. https://doi.org/10.1093/braincomms/fcaa124.
47. Beers DR, Zhao W, Wang J, et al. ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity. JCI Insight. 2017;2(5):e89530. https://doi.org/10.1172/jci. insight.89530.
48. Jin M, Günther R, Akgün K, et al. Peripheral proinflammatory Th1/Th17 immune cell shift is linked to disease severity in amyotrophic lateral sclerosis. Sci Rep. 2020;10(1):5941. https://doi.org/10.1038/s41598-020-62756-8.
49. Duque T, Gromicho M, Pronto-Laborinho AC, de Carvalho M. Transforming growth factor-ß plasma levels and its role in amyotrophic lateral sclerosis. Med Hypotheses. 2020;139:109632. https://doi.org/10.1016/j. mehy.2020.109632.
50. Beswick EJ, Pinchuk IV, Earley RB, et al. Role of gastric epithelial cell-derived transforming growth factor beta in reduced CD4 + T cell proliferation and development of regulatory T cells during Helicobacter pylori infection. Infect Immun. 2011;79(7):2737–45. https://doi.org/10.1128/IAI.01146-10.
51. Alatrakchi N, Graham CS, van der Vliet HJ, et al. Hepatitis C virus (HCV)-specific CD8 + cells produce transforming growth factor beta that can suppress HCVspecific T-cell responses. J Virol. 2007;81(11):5882–92. https://doi.org/10.1128/JVI.02202-06.
52. Khorramdelazad H, Hassanshahi G, Nasiri Ahmadabadi B, Kazemi Arababadi M. High serum levels of TGF- ß in Iranians with chronic HBV infection. Hepat Mon. 2012;12(11):e7581. https://doi.org/10.5812/hepatmon.7581.
53. Karimi-Googheri M, Daneshvar H, Nosratabadi R, et al. Important roles played by TGF-ß in hepatitis B infection. J Med Virol. 2014;86(1):102–8. https://doi.org/10.1002/jmv.23727.
54. Si Y, Kim S, Cui X, et al. Transforming growth factor beta (TGF-ß) is a muscle biomarker of disease progression in ALS and correlates with Smad expression. PLoS One. 2015;10(9):e0138425. https://doi.org/10.1371/journal. pone.0138425.
55. Rosenbohm A, Schmid B, Buckert D, et al. Cardiac findings in amyotrophic lateral sclerosis: a magnetic resonance imaging study. Front Neurol. 2017;8:479. https://doi.org/10.3389/fneur.2017.00479.
56. Budzynski J, Wisniewska J, Ciecierski M, Kedzia A. Association between bacterial infection and peripheral vascular disease: a review. Int J Angiol. 2016;25(1): 3–13. https://doi.org/10.1055/s-0035-1547385.
57. Fukui Y, Hishikawa N, Shang J, et al. Peripheral arterial endothelial dysfunction of neurodegenerative diseases. J Neurol Sci. 2016;366:94–9. https://doi.org/10.1016/j. jns.2016.04.042.
58. Yamadera M, Fujimura H, Inoue K, et al. Microvascular disturbance with decreased pericyte coverage is prominent in the ventral horn of patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5–6):393–401. https://doi.org/10.3109/21678421.2015.1011663.
59. Schmid B, Hruscha A, Hogl S, et al. Loss of ALSassociated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth. Proc Natl Acad Sci U S A. 2013;110(13):4986–91. https://doi.org/10.1073/pnas.1218311110.
60. Umahara T, Uchihara T, Hirao K, et al. Frontotemporal dementia-associated protein "phosphorylated TDP- 43" localizes to atherosclerotic lesions of human carotid and main cerebral arteries. Histol Histopathol. 2020;35(2):159–67. https://doi.org/10.14670/HH-18-140.
61. McKee AC, Gavett BE, Stern RA, et al. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. 2010;69(9):918–29. https://doi.org/10.1097/NEN.0b013e3181ee7d85.
62. Pupillo E, Poloni M, Bianchi E, et al. Trauma and amyotrophic lateral sclerosis: a European populationbased case-control study from the EURALS consortium. Amyotroph Lateral Scler Frontotemporal Degener. 2018;19(1–2):118–25. https://doi.org/10.1080/21678421. 2017.1386687.
63. Winkler EA, Sengillo JD, Sullivan JS, et al. Bloodspinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol. 2013;125(1):111–20. https://doi.org/10.1007/s00401-012-1039-8.
64. Heyburn L, Abutarboush R, Goodrich S, et al. Repeated low-level blast overpressure leads to endovascular disruption and alterations in TDP-43 and Piezo2 in a rat model of blast TBI. Front Neurol. 2019;10:766. https://doi.org/10.3389/fneur.2019.00766.
65. Aundhakar SC, Mahajan SK, Chhapra DA. Hirayama’s disease: a rare clinical variant of amyotrophic lateral sclerosis. Adv Biomed Res. 2017;6:95. https://doi.org/10.4103/2277-9175.211797.
66. Storti B, Diamanti S, Tremolizzo L, et al. ALS mimics due to affection of the cervical spine: from common compressive myelopathy to rare CSF epidural collection. Case Rep Neurol. 2021;13(1):145–56. https://doi.org/10.1159/000512810.
67. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid ß. Sci Transl Med. 2012;4(147):147ra111. https://doi.org/10.1126/scitranslmed.3003748.
68. Pappolla M, Sambamurti K, Vidal R, et al. Evidence for lymphatic Aß clearance in Alzheimer’s transgenic mice. Neurobiol Dis. 2014;71:215–9. https://doi.org/10.1016/j. nbd.2014.07.012.
69. de Leon MJ, Li Y, Okamura N, et al. Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET. J Nucl Med. 2017;58(9):1471–6. https://doi.org/10.2967/jnumed.116.187211.
70. Zou W, Pu T, Feng W, et al. Blocking meningeal lymphatic drainage aggravates Parkinson’s disease-like pathology in mice overexpressing mutated a-synuclein. Transl Neurodegener. 2019;8:7. https://doi.org/10.1186/s40035-019-0147-y.
71. Sass LR, Khani M, Romm J, et al. Non-invasive MRI quantification of cerebrospinal fluid dynamics in amyotrophic lateral sclerosis patients. Fluids Barriers CNS. 2020;17(1):4. https://doi.org/10.1186/s12987-019-0164-3.
72. Flanagan MF. The role of the craniocervical junction in craniospinal hydrodynamics and neurodegenerative conditions. Neurol Res Int. 2015;2015:794829. https://doi.org/10.1155/2015/794829.
73. Holzapfel K, Naumann M. Ultrasound detection of vagus nerve atrophy in bulbar amyotrophic lateral sclerosis. J Neuroimaging. 2020;30(6):762–5. https://doi.org/10.1111/jon.12761.
74. Pathak S, Tripathi S, Deori N, et al. Effect of tetracycline family of antibiotics on actin aggregation, resulting in the formation of Hirano bodies responsible for neuropathological disorders. J Biomol Struct Dyn. 2021;39(1):236–53. https://doi.org/10.1080/07391102.2020.1717629.
75. Altman T, Ionescu A, Ibraheem A, et al. Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins. Nat Commun. 2021;12(1):6914. https://doi.org/10.1038/s41467-021-27221-8.
76. Ng HY, Oliver BG, Burgess JK, et al. Doxycycline reduces the migration of tuberous sclerosis complex-2 null cells - effects on RhoA-GTPase and focal adhesion kinase. J Cell Mol Med. 2015;19(11):2633–46. https://doi.org/10.1111/jcmm.12593.
77. González-Lizárraga F, Socías SB, Ávila CL, et al. Repurposing doxycycline for synucleinopathies: remodelling of a-synuclein oligomers towards nontoxic parallel beta-sheet structured species. Sci Rep. 2017;7:41755. https://doi.org/10.1038/srep41755.
78. Das AT, Tenenbaum L, Berkhout B. Tet-On systems for doxycycline-inducible gene expression. Curr Gene Ther. 2016;16(3):156–67. https://doi.org/10.2174/1566523216 666160524144041.
79. Gasparrini AJ, Markley JL, Kumar H, et al. Tetracycline-inactivating enzymes from environmental, human commensal, and pathogenic bacteria cause broad-spectrum tetracycline resistance. Commun Biol. 2020;3(1):241. https://doi.org/10.1038/s42003-020-0966-5.
80. Stone LK, Baym M, Lieberman TD, et al. Compounds that select against the tetracycline-resistance efflux pump. Nat Chem Biol. 2016;12(11):902–4. https://doi.org/10.1038/nchembio.2176.
81. Domon H, Hiyoshi T, Maekawa T, et al. Antibacterial activity of hinokitiol against both antibioticresistant and -susceptible pathogenic bacteria that predominate in the oral cavity and upper airways. Microbiol Immunol. 2019;63(6):213–22. https://doi.org/10.1111/1348-0421.12688.
82. Kim DJ, Lee MW, Choi JS, et al. Inhibitory activity of hinokitiol against biofilm formation in fluconazole-resistant Candida species. PLoS One. 2017;12(2):e0171244. https://doi.org/10.1371/journal.pone.0171244.
83. Lee JH, Jeong JK, Park SY. AMPK Activation mediated by hinokitiol inhibits adipogenic differentiation of mesenchymal stem cells through autophagy flux. Int J Endocrinol. 2018;2018:2014192. https://doi.org/10.1155/2018/2014192.
84. Moon JH, Lee JH, Lee YJ, Park SY. Hinokitiol protects primary neuron cells against prion peptide-induced toxicity via autophagy flux regulated by hypoxia inducing factor-1. Oncotarget. 2016;7(21):29944–57. https://doi.org/10.18632/oncotarget.8670.
85. Grillo AS, SantaMaria AM, Kafina MD, et al. Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals. Science. 2017;356(6338):608–16. https://doi.org/10.1126/science. aah3862.
86. Zhou J, Lu Y, Wu W, Feng Y. Taurine promotes the production of CD4 + CD25 + FOXP3 + Treg cells through regulating IL-35/STAT1 pathway in a mouse allergic rhinitis model. Allergy Asthma Clin Immunol. 2021;17(1):59. https://doi.org/10.1186/s13223-021-00562-1.
87. Kato J, Ido A, Hasuike S, et al. Transforming growth factor-beta-induced stimulation of formation of collagen fiber network and anti-fibrotic effect of taurine in an in vitro model of hepatic fibrosis. Hepatol Res. 2004;30(1):34–41. https://doi.org/10.1016/j. hepres.2004.04.006.
88. Jung MK, Kim KY, Lee NY, et al. Expression of taurine transporter (TauT) is modulated by heat shock factor 1 (HSF1) in motor neurons of ALS. Mol Neurobiol. 2013;47(2):699–710. https://doi.org/10.1007/s12035-012-8371-9.
89. Kim W, Kim HU, Lee HN, et al. Taurine chloramine stimulates efferocytosis through upregulation of Nrf2- mediated heme oxygenase-1 expression in murine macrophages: possible involvement of carbon monoxide. Antioxid Redox Signal. 2015;23(2):163–77. https://doi.org/10.1089/ars.2013.5825.
90. Boussicault L, Laffaire J, Schmitt P, et al. Combination of acamprosate and baclofen (PXT864) as a potential new therapy for amyotrophic lateral sclerosis. J Neurosci Res. 2020;98(12):2435–50. https://doi.org/10.1002/jnr.24714.
91. Kalk NJ, Lingford-Hughes AR. The clinical pharmacology of acamprosate. Br J Clin Pharmacol. 2014;77(2):315–23. https://doi.org/10.1111/bcp.12070.
92. Lienhart WD, Gudipati V, Macheroux P. The human flavoproteome. Arch Biochem Biophys. 2013;535(2):150162. https://doi.org/10.1016/j.abb.2013.02.015.
93. Lei J, Xin C, Xiao W, et al. The promise of endogenous and exogenous riboflavin in antiinfection. Virulence. 2021;12(1):2314–26. https://doi.org/10.1080/21505594.2 021.1963909.
94. Depeint F, Bruce WR, Shangari N, et al. Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism. Chem Biol Interact. 2006;163(1-2):94–112. https://doi.org/10.1016/j. cbi.2006.04.014.
95. Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015;17(9):689–701. https://doi.org/10.1038/gim.2014.177.
96. Rizzo F, Ramirez A, Compagnucci C, et al. Genomewide RNA-seq of iPSC-derived motor neurons indicates selective cytoskeletal perturbation in Brown-Vialetto disease that is partially rescued by riboflavin. Sci Rep. 2017;7:46271. https://doi.org/10.1038/srep46271.
97. Carreau C, Lenglet T, Mosnier I, et al. A juvenile ALS-like phenotype dramatically improved after high-dose riboflavin treatment. Ann Clin Transl Neurol. 2020;7(2):250–3. https://doi.org/10.1002/acn3.50977.
98. Toyosawa T, Suzuki M, Kodama K, Araki S. Effects of intravenous infusion of highly purified vitamin B2 on lipopolysaccharide-induced shock and bacterial infection in mice. Eur J Pharmacol. 2004;492(2–3):273–80. https://doi.org/10.1016/j.ejphar.2004.04.004.
99. Lee ER, Blount KF, Breaker RR. Roseoflavin is a natural antibacterial compound that binds to FMN riboswitches and regulates gene expression. RNA Biol. 2009;6(2):187– 94. https://doi.org/10.4161/rna.6.2.7727.
100. Scafidi S, Fiskum G, Lindauer SL, et al. Metabolism of acetyl-L-carnitine for energy and neurotransmitter synthesis in the immature rat brain. J Neurochem. 2010;114(3):820–31. https://doi.org/10.1111/j.1471-4159.2010.06807.x.
101. Borghi-Silva A, Baldissera V, Sampaio LM, et al. L-carnitine as an ergogenic aid for patients with chronic obstructive pulmonary disease submitted to whole-body and respiratory muscle training programs. Braz J Med Biol Res. 2006;39(4):465–74. https://doi.org/10.1590/s0100-879x2006000400006.
102. Bavbek N, Akay H, Uz B, et al. The effects of L-carnitine therapy on respiratory function tests in chronic hemodialysis patients. Ren Fail. 2010;32(2):157–61. https://doi.org/10.3109/08860221003592812.
103. Ogle RF, Christodoulou J, Fagan E, et al. Mitochondrial myopathy with tRNA(Leu(UUR)) mutation and complex I deficiency responsive to riboflavin. J Pediatr. 1997;130(1):138–45. https://doi.org/10.1016/s00223476(97)70323-8.
104. Shimokawa H, Sunamura S, Satoh K. RhoA/Rho-kinase in the cardiovascular system. Circ Res. 2016;118(2):352– 66. https://doi.org/10.1161/CIRCRESAHA.115.306532.
105. Masumoto A, Mohri M, Shimokawa H, et al. Suppression of coronary artery spasm by the Rhokinase inhibitor fasudil in patients with vasospastic angina. Circulation. 2002;105(13):1545–7. https://doi.org/10.1161/hc1002.105938.
106. Olson MF. Applications for ROCK kinase inhibition. Curr Opin Cell Biol. 2008;20(2):242–8. https://doi.org/10.1016/j.ceb.2008.01.002.
107. Suzuki Y, Shibuya M, Satoh S, et al. Safety and efficacy of fasudil monotherapy and fasudil-ozagrel combination therapy in patients with subarachnoid hemorrhage: sub-analysis of the postmarketing surveillance study. Neurol Med Chir (Tokyo). 2008;48(6):241–8. https://doi.org/10.2176/nmc.48.241.
108. Velat GJ, Kimball MM, Mocco JD, Hoh BL. Vasospasm after aneurysmal subarachnoid hemorrhage: review of randomized controlled trials and meta-analyses in the literature. World Neurosurg. 2011;76(5):446–54. https://doi.org/10.1016/j.wneu.2011.02.030.
109. Rao PV, Pattabiraman PP, Kopczynski C. Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: bench to bedside research. Exp Eye Res. 2017;158:23–32. https://doi.org/10.1016/j.exer.2016.08.023.
110. Stankiewicz TR, Ramaswami SA, Bouchard RJ, et al. Neuronal apoptosis induced by selective inhibition of Rac GTPase versus global suppression of Rho family GTPases is mediated by alterations in distinct mitogenactivated protein kinase signaling cascades. J Biol Chem. 2015;290(15):9363–76. https://doi.org/10.1074/jbc. M114.575217.
111. Markovinovic A, Cimbro R, Ljutic T, et al. Optineurin in amyotrophic lateral sclerosis: Multifunctional adaptor protein at the crossroads of different neuroprotective mechanisms. Prog Neurobiol. 2017;154:1–20. https://doi.org/10.1016/j.pneurobio.2017.04.005.
112. Slowicka K, Vereecke L, van Loo G. Cellular functions of optineurin in health and disease. Trends Immunol. 2016;37(9):621–33. https://doi.org/10.1016/j. it.2016.07.002.
113. Toth RP, Atkin JD. Dysfunction of optineurin in amyotrophic lateral sclerosis and glaucoma. Front Immunol. 2018;9:1017. https://doi.org/10.3389/fimmu.2018.01017.
114. Lingor P, Weber M, Camu W, et al. ROCK-ALS: Protocol for a randomized, placebo-controlled, doubleblind phase IIa trial of safety, tolerability and efficacy of the Rho kinase (ROCK) inhibitor fasudil in amyotrophic lateral sclerosis. Front Neurol. 2019;10:293. https://doi.org/10.3389/fneur.2019.00293.
115. Kulkarni SK, Dhir A. sigma-1 receptors in major depression and anxiety. Expert Rev Neurother. 2009;9(7):1021–34. https://doi.org/10.1586/ern.09.40.
116. Huang L, Zhang X, Ma X, et al. Berberine alleviates endothelial glycocalyx degradation and promotes glycocalyx restoration in LPS-induced ARDS. Int Immunopharmacol. 2018;65:96–107. https://doi.org/10.1016/j.intimp.2018.10.001.
117. Jin Y, Liu S, Ma Q, et al. Berberine enhances the AMPK activation and autophagy and mitigates high glucose-induced apoptosis of mouse podocytes. Eur J Pharmacol. 2017;794:106–14. https://doi.org/10.1016/j. ejphar.2016.11.037.
118. Chang CF, Lee YC, Lee KH, et al. Therapeutic effect of berberine on TDP-43-related pathogenesis in FTLD and ALS. J Biomed Sci. 2016;23(1):72. https://doi.org/10.1186/s12929-016-0290-z.
119. Rusmini P, Cristofani R, Tedesco B, et al. Enhanced clearance of neurotoxic misfolded proteins by the natural compound berberine and its derivatives. Int J Mol Sci. 2020;21(10):3443. https://doi.org/10.3390/ijms21103443.
120. Zeng P, Zhou X. Causal effects of blood lipids on amyotrophic lateral sclerosis: a Mendelian randomization study. Hum Mol Genet. 2019;28(4):688–97. https://doi.org/10.1093/hmg/ddy384.
121. Hope J. A review of the mechanism of injury and treatment approaches for illness resulting from exposure to water-damaged buildings, mold, and mycotoxins. ScientificWorldJournal. 2013;2013:767482. https://doi.org/10.1155/2013/767482.
122. Rezai AR, Ranjan M, D’Haese PF, et al. Noninvasive hippocampal blood-brain barrier opening in Alzheimer’s disease with focused ultrasound. Proc Natl Acad Sci U S A. 2020;117(17):9180–2. https://doi.org/10.1073/pnas.2002571117.
123. Yu FTH, Chen X, Straub AC, Pacella JJ. The role of nitric oxide during sonoreperfusion of microvascular obstruction. Theranostics. 2017;7(14):3527–38. https://doi.org/10.7150/thno.19422.
124. Beggs CB. Venous hemodynamics in neurological disorders: an analytical review with hydrodynamic analysis. BMC Med. 2013;11:142. https://doi.org/10.1186/1741-7015-11-142.
125. Nichols NL, Van Dyke J, Nashold L, et al. Ventilatory control in ALS. Respir Physiol Neurobiol. 2013;189(2):429–437. https://doi.org/10.1016/j. resp.2013.05.016.
126. de Carvalho M, Swash M, Pinto S. Diaphragmatic neurophysiology and respiratory markers in ALS. Front Neurol. 2019;10:143. https://doi.org/10.3389/fneur.2019.00143.
127. Niedermeyer S, Murn M, Choi PJ. Respiratory failure in amyotrophic lateral sclerosis. Chest. 2019;155(2):401–8. https://doi.org/10.1016/j.chest.2018.06.035.
128. Puls I, Beck M, Giess R, et al. Clenbuterol bei der Amyotrophen Lateralsklerose. Kein Hinweis für einen positiven Effekt [Clenbuterol in amyotrophic lateral sclerosis. No indication for a positive effect]. Nervenarzt. 1999;70(12):1112–5. https://doi.org/10.1007/s001150050548.
129. Zafar A, Zulfiqar H. Aminophylline. [Updated 2022 Jan 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK545175/.
130. Golder FJ, Ranganathan L, Satriotomo I, et al. Spinal adenosine A2a receptor activation elicits long-lasting phrenic motor facilitation. J Neurosci. 2008;28(9):2033–42. https://doi.org/10.1523/JNEUROSCI.3570-07.2008.
131. Berto MC, Filha SC, Camelier A, et al. Acute action of aminophylline in patients with amyotrophic lateral sclerosis. Acta Neurol Scand. 2007;115(5):301–5. https://doi.org/10.1111/j.1600-0404.2007.00643.x.
132. Massey EW, Lowe S. Lithium carbonate in pseudobulbar palsy. Ann Neurol. 1981;9(1):97. https://doi.org/10.1002/ana.410090128.
133. Liu M, Qian T, Zhou W, et al. Beneficial effects of low-dose lithium on cognitive ability and pathological alteration of Alzheimer’s disease transgenic mice model. Neuroreport. 2020;31(13):943–51. https://doi.org/10.1097/WNR.0000000000001499.
134. Moutal A, White KA, Chefdeville A, et al. Dysregulation of CRMP2 post-translational modifications drive its pathological functions. Mol Neurobiol. 2019;56(10):6736–55. https://doi.org/10.1007/s12035-019-1568-4.
135. Lin PC, Chan PM, Hall C, Manser E. Collapsin response mediator proteins (CRMPs) are a new class of microtubule- associated protein (MAP) that selectively interacts with assembled microtubules via a taxolsensitive binding interaction. J Biol Chem. 2011;286(48):41466–78. https://doi.org/10.1074/jbc.M111.283580.
136. Nakamura F, Ohshima T, Goshima Y. Collapsin response mediator proteins: their biological functions and pathophysiology in neuronal development and regeneration. Front Cell Neurosci. 2020;14:188. https://doi.org/10.3389/fncel.2020.00188.
137. Brot S, Auger C, Bentata R, et al. Collapsin response mediator protein 5 (CRMP5) induces mitophagy, thereby regulating mitochondrion numbers in dendrites. J Biol Chem. 2014;289(4):2261–76. https://doi.org/10.1074/jbc. M113.490862.
138. Alabed YZ, Pool M, Ong Tone S, Fournier AE. Identification of CRMP4 as a convergent regulator of axon outgrowth inhibition. J Neurosci. 2007;27(7):1702–11. https://doi.org/10.1523/JNEUROSCI.5055-06.2007.
139. Numata-Uematsu Y, Wakatsuki S, Nagano S, et al. Inhibition of collapsin response mediator protein-2 phosphorylation ameliorates motor phenotype of ALS model mice expressing SOD1G93A. Neurosci Res. 2019;139:63–8. https://doi.org/10.1016/j. neures.2018.08.016.
140. Arimura N, Ménager C, Kawano Y, et al. Phosphorylation by Rho kinase regulates CRMP-2 activity in growth cones. Mol Cell Biol. 2005;25(22):9973–84. https://doi.org/10.1128/MCB.25.22.9973-9984.2005.
141. Yang W, Leystra-Lantz C, Strong MJ. Upregulation of GSK3beta expression in frontal and temporal cortex in ALS with cognitive impairment (ALSci). Brain Res. 2008;1196:131–9. https://doi.org/10.1016/j. brainres.2007.12.031.
142. He Z, Zhou Y, Wang Q, et al. Inhibiting endoplasmic reticulum stress by lithium chloride contributes to the integrity of blood-spinal cord barrier and functional recovery after spinal cord injury. Am J Transl Res. 2017;9(3):1012–24. PMID: 28386329.
143. Tong M, He Z, Lin X, et al. Lithium chloride contributes to blood-spinal cord barrier integrity and functional recovery from spinal cord injury by stimulating autophagic flux. Biochem Biophys Res Commun. 2018;495(4):2525–31. https://doi.org/10.1016/j. bbrc.2017.12.119.
144. Fornai F, Longone P, Cafaro L, et al. Lithium delays progression of amyotrophic lateral sclerosis [published correction appears in Proc Natl Acad Sci U S A. 2008 21;105(42):16404–7]. Proc Natl Acad Sci U S A. 2008;105(6):2052–7. https://doi.org/10.1073/pnas.0708022105.
145. Pasquali L, Longone P, Isidoro C, et al. Autophagy, lithium, and amyotrophic lateral sclerosis. Muscle Nerve. 2009;40(2):173–94. https://doi.org/10.1002/mus.21423.
146. Devanand DP, Pelton GH, D’Antonio K, et al. Lowdose lithium treatment for agitation and psychosis in Alzheimer disease and frontotemporal dementia: a case series. Alzheimer Dis Assoc Disord. 2017;31(1):73–5. https://doi.org/10.1097/WAD.0000000000000161.
147. van Eijk RPA, Jones AR, Sproviero W, et al. Metaanalysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials [published correction appears in Neurology. 2017;89(22):2303]. Neurology. 2017;89(18):1915–22. https://doi.org/10.1212/WNL.0000000000004606.
148. Limanaqi F, Biagioni F, Ryskalin L, et al. Molecular mechanisms linking ALS/FTD and psychiatric disorders, the potential effects of lithium. Front Cell Neurosci. 2019;13:450. https://doi.org/10.3389/fncel.2019.00450.
149. Ionescu A, Gradus T, Altman T, et al. Targeting the sigma-1 receptor via pridopidine ameliorates central features of ALS pathology in a SOD1G93A model. Cell Death Dis. 2019;10(3):210. https://doi.org/10.1038/s41419-019-1451-2.
150. Mancuso R, Oliván S, Rando A, et al. Sigma-1R agonist improves motor function and motoneuron survival in ALS mice. Neurotherapeutics. 2012;9(4):814–26. https://doi.org/10.1007/s13311-012-0140-y.
151. Ono Y, Tanaka H, Takata M, et al. SA4503, a sigma-1 receptor agonist, suppresses motor neuron damage in in vitro and in vivo amyotrophic lateral sclerosis models. Neurosci Lett. 2014;559:174–8. https://doi.org/10.1016/j. neulet.2013.12.005.
152. Mavlyutov TA, Guo LW, Epstein ML, Ruoho AE. Role of the sigma-1 receptor in amyotrophic lateral sclerosis (ALS). J Pharmacol Sci. 2015;127(1):10–6. https://doi.org/10.1016/j.jphs.2014.12.013.
153. Liu DY, Chi TY, Ji XF, et al. Sigma-1 receptor activation alleviates blood-brain barrier dysfunction in vascular dementia mice. Exp Neurol. 2018;308:90–9. https://doi.org/10.1016/j.expneurol.2018.07.002.
154. Vandoorne T, De Bock K, Van Den Bosch L. Energy metabolism in ALS: an underappreciated opportunity? Acta Neuropathol. 2018;135(4):489–509. https://doi.org/10.1007/s00401-018-1835-x.
155. Patel BP, Safdar A, Raha S, et al. Caloric restriction shortens lifespan through an increase in lipid peroxidation, inflammation and apoptosis in the G93A mouse, an animal model of ALS. PLoS One. 2010;5(2):e9386. https://doi.org/10.1371/journal.pone.0009386.
156. Coughlan KS, Halang L, Woods I, Prehn JH. A high-fat jelly diet restores bioenergetic balance and extends lifespan in the presence of motor dysfunction and lumbar spinal cord motor neuron loss in TDP-43A315T mutant C57BL6/J mice. Dis Model Mech. 2016;9(9):1029–37. https://doi.org/10.1242/dmm.024786.
157. Dupuis L, Oudart H, René F, et al. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004;101(30):11159– 64. https://doi.org/10.1073/pnas.0402026101.
158. Wills AM, Hubbard J, Macklin EA, et al. Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet. 2014;383(9934):2065–72. https://doi.org/10.1016/S0140-736(14)60222-1.
159. Calignano A, La Rana G, Piomelli D. Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide. Eur J Pharmacol. 2001;419(2–3):191–8. https://doi.org/10.1016/s0014-2999(01)00988-8.
160. Sabelli H, Fink P, Fawcett J, Tom C. Sustained antidepressant effect of PEA replacement. J Neuropsychiatry Clin Neurosci. 1996;8(2):168–71. https://doi.org/10.1176/jnp.8.2.168.
161. Lin TY, Lu CW, Wu CC, et al. Palmitoylethanolamide inhibits glutamate release in rat cerebrocortical nerve terminals. Int J Mol Sci. 2015;16(3):5555–71. https://doi.org/10.3390/ijms16035555.
162. Palma E, Reyes-Ruiz JM, Lopergolo D, et al. Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy. Proc Natl Acad Sci U S A. 2016;113(11):3060–5. https://doi.org/10.1073/pnas.1600251113.
163. Giannoni A, Borrelli C, Mirizzi G, et al. Benefit of buspirone on chemoreflex and central apnoeas in heart failure: a randomized controlled crossover trial. Eur J Heart Fail. 2021;23(2):312320. https://doi.org/10.1002/ejhf.1854.
164. Maresh S, Prowting J, Vaughan S, et al. Buspirone decreases susceptibility to hypocapnic central sleep apnea in chronic SCI patients. J Appl Physiol (1985). 2020;129(4):675–82. https://doi.org/10.1152/japplphysiol.00435.2020.
165. Vollrath JT, Sechi A, Dreser A, et al. Loss of function of the ALS protein SigR1 leads to ER pathology associated with defective autophagy and lipid raft disturbances. Cell Death Dis. 2014;5(6):e1290. https://doi.org/10.1038/cddis.2014.243.
166. Meininger V, Bensimon G, Bradley WR, et al. Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004;5(2):107117. https://doi.org/10.1080/14660820410019602.
167. Langade D, Thakare V, Kanchi S, Kelgane S. Clinical evaluation of the pharmacological impact of ashwagandha root extract on sleep in healthy volunteers and insomnia patients: A double-blind, randomized, parallelgroup, placebo-controlled study. J Ethnopharmacol. 2021;264:113276. https://doi.org/10.1016/j. jep.2020.113276.
168. Bale S, Venkatesh P, Sunkoju M, Godugu C. An adaptogen: withaferin A ameliorates in vitro and in vivo pulmonary fibrosis by modulating the interplay of fibrotic, matricelluar proteins, and cytokines. Front Pharmacol. 2018;9:248. https://doi.org/10.3389/fphar.2018.00248.
169. Behl T, Sharma A, Sharma L, et al. Exploring the multifaceted therapeutic potential of withaferin A and its derivatives. Biomedicines. 2020;8(12):571. https://doi.org/10.3390/biomedicines8120571.
170. Kumar S, Phaneuf D, Cordeau P Jr, et al. Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD. Mol Neurodegener. 2021;16(1):1. https://doi.org/10.1186/s13024-020-00420-5.
171. Pinato L, da Silveira Cruz-Machado S, Franco DG, et al. Selective protection of the cerebellum against intracerebroventricular LPS is mediated by local melatonin synthesis. Brain Struct Funct. 2015;220(2):827–40. https://doi.org/10.1007/s00429-013-0686-4.
172. Hu Y, Wang Z, Pan S, et al. Melatonin protects against blood-brain barrier damage by inhibiting the TLR4 NF?B signaling pathway after LPS treatment in neonatal rats. Oncotarget. 2017;8(19):31638–54. https://doi.org/10.18632/oncotarget.15780.
173. Sagrillo-Fagundes L, Bienvenue-Pariseault J, Vaillancourt C. Melatonin: the smart molecule that differentially modulates autophagy in tumor and normal placental cells. PLoS One. 2019;14(1):e0202458. https://doi.org/10.1371/journal.pone.0202458.
174. Bald EM, Nance CS, Schultz JL. Melatonin may slow disease progression in amyotrophic lateral sclerosis: findings from the pooled resource open-access ALS clinic trials database. Muscle Nerve. 2021;63(4):572576. https://doi.org/10.1002/mus.27168.
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