Rethinking ALS: Current understanding and emerging therapeutic strategies

Arosh S. Perera Molligoda Arachchige; Arosh S. Perera Molligoda Arachchige

doi:10.3934/Neuroscience.2025021

AIMS Neuroscience

2025, Volume 12, Issue 3: 391-405. doi: 10.3934/Neuroscience.2025021

Previous Article Next Article

Review Topical Sections

Rethinking ALS: Current understanding and emerging therapeutic strategies

Arosh S. Perera Molligoda Arachchige ^,

Faculty of Medicine, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Lombardy, Italy

Received: 07 August 2025 Revised: 16 September 2025 Accepted: 22 September 2025 Published: 25 September 2025

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of the upper and lower motor neurons, which leads to muscle atrophy, spasticity, and ultimately respiratory failure. The etiology of ALS remains unclear, though a combination of genetic and environmental factors is suspected. Advances in understanding ALS pathophysiology, including the role of RNA metabolism, mitochondrial dysfunction, and glutamate toxicity, have paved the way for new research directions. While Riluzole offers limited survival benefits, there is no cure, and treatment remains mostly supportive. This article summarizes the current understanding of ALS in terms of its pathophysiology, epidemiology, risk factors, clinical presentation, and treatment strategies.
- amyotrophic lateral sclerosis,
- motor neuron disease,
- neurodegeneration,
- Riluzole,
- RNA metabolism
Citation: Arosh S. Perera Molligoda Arachchige. Rethinking ALS: Current understanding and emerging therapeutic strategies[J]. AIMS Neuroscience, 2025, 12(3): 391-405. doi: 10.3934/Neuroscience.2025021

Related Papers:

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degeneration of the upper and lower motor neurons, which leads to muscle atrophy, spasticity, and ultimately respiratory failure. The etiology of ALS remains unclear, though a combination of genetic and environmental factors is suspected. Advances in understanding ALS pathophysiology, including the role of RNA metabolism, mitochondrial dysfunction, and glutamate toxicity, have paved the way for new research directions. While Riluzole offers limited survival benefits, there is no cure, and treatment remains mostly supportive. This article summarizes the current understanding of ALS in terms of its pathophysiology, epidemiology, risk factors, clinical presentation, and treatment strategies.

Conflict of interest

The authors declare no conflict of interest.

References

[1]	Boillée S, Vande Velde C, Cleveland DW (2006) ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52: 39-59. https://doi.org/10.1016/j.neuron.2006.09.018
[2]	Cleveland DW, Rothstein JD (2001) From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci 2: 806-819. https://doi.org/10.1038/35097565
[3]	Bradley WG (2009) Updates on amyotrophic lateral sclerosis: improving patient care. Ann Neurol 65 Suppl 1: S1-2. https://doi.org/10.1002/ana.21546
[4]	Hardiman O, Al-Chalabi A, Chio A, et al. (2017) Amyotrophic lateral sclerosis. Nat Rev Dis Primers 3: 17071. https://doi.org/10.1038/nrdp.2017.71
[5]	Noor Eddin A, Alfuwais M, Noor Eddin R, et al. (2024) Gut-Modulating Agents and Amyotrophic Lateral Sclerosis: Current Evidence and Future Perspectives. Nutrients 16: 590. https://doi.org/10.3390/nu16050590
[6]	Grad LI, Rouleau GA, Ravits J, et al. (2017) Clinical Spectrum of Amyotrophic Lateral Sclerosis (ALS). Cold Spring Harb Perspect Med 7: a024117. https://doi.org/10.1101/cshperspect.a024117
[7]	Wijesekera LC, Leigh PN (2009) Amyotrophic lateral sclerosis. Orphanet J Rare Dis 4: 3. https://doi.org/10.1186/1750-1172-4-3
[8]	Sacks B, Bashford J, Wijesekera L, et al. (2021) Motor Neuron Disease: Amyotrophic Lateral Sclerosis. Neuroscience in the 21st Century . New York, NY: Springer. https://doi.org/10.1007/978-1-4614-6434-1_111-3
[9]	Wang X, Hu Y, Xu R (2024) The pathogenic mechanism of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis. Neural Regen Res 19: 800-806. https://doi.org/10.4103/1673-5374.382233
[10]	Harjuhaahto S, Rasila TS, Molchanova SM, et al. (2020) ALS and Parkinson's disease genes CHCHD10 and CHCHD2 modify synaptic transcriptomes in human iPSC-derived motor neurons. Neurobiol Dis 141: 104940. https://doi.org/10.1016/j.nbd.2020.104940
[11]	Arnold FJ, Putka AF, Raychaudhuri U, et al. (2024) Revisiting Glutamate Excitotoxicity in Amyotrophic Lateral Sclerosis and Age-Related Neurodegeneration. Int J Mol Sci 25: 5587. https://doi.org/10.3390/ijms25115587
[12]	You J, Youssef MMM, Santos JR, et al. (2023) Microglia and Astrocytes in Amyotrophic Lateral Sclerosis: Disease-Associated States, Pathological Roles, and Therapeutic Potential. Biology (Basel) 12: 1307. https://doi.org/10.3390/biology12101307
[13]	Rossi S, Cozzolino M (2021) Dysfunction of RNA/RNA-Binding Proteins in ALS Astrocytes and Microglia. Cells 10: 3005. https://doi.org/10.3390/cells10113005
[14]	Rojas P, Ramírez AI, Fernández-Albarral JA, et al. (2020) Amyotrophic Lateral Sclerosis: A Neurodegenerative Motor Neuron Disease With Ocular Involvement. Front Neurosci 14: 566858. https://doi.org/10.3389/fnins.2020.566858
[15]	Ingre C, Roos PM, Piehl F, et al. (2015) Risk factors for amyotrophic lateral sclerosis. Clin Epidemiol 7: 181-193. https://doi.org/10.2147/CLEP.S37505
[16]	Kiernan MC, Vucic S, Cheah BC, et al. (2011) Amyotrophic lateral sclerosis. Lancet 377: 942-955. https://doi.org/10.1016/S0140-6736(10)61156-7
[17]	Garruto RM, Gajdusek C, Chen KM (1980) Amyotrophic lateral sclerosis among Chamorro migrants from Guam. Ann Neurol 8: 612-619. https://doi.org/10.1002/ana.410080612
[18]	Feit H (1983) ALS and parkinsonian syndromes among the Auyu and Jakai. Neurology 33: 812. https://doi.org/10.1212/WNL.33.6.812
[19]	Hanhisuanto M, Solje E, Jokela M, et al. (2023) Amyotrophic Lateral Sclerosis in Southwestern and Eastern Finland. Neuroepidemiology 57: 238-245. https://doi.org/10.1159/000531238
[20]	Spencer PS, Lagrange E, Camu W (2019) ALS and environment: Clues from spatial clustering?. Rev Neurol (Paris) 175: 652-663. https://doi.org/10.1016/j.neurol.2019.04.007
[21]	Bozzoni V, Pansarasa O, Diamanti L, et al. (2016) Amyotrophic lateral sclerosis and environmental factors. Funct Neurol 31: 7-19. https://doi.org/10.11138/FNeur/2016.31.1.007
[22]	Duan QQ, Jiang Z, Su WM, et al. (2023) Risk factors of amyotrophic lateral sclerosis: a global meta-summary. Front Neurosci 17: 1177431. https://doi.org/10.3389/fnins.2023.1177431
[23]	Huang M, Liu YU, Yao X, et al. (2024) Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications. Transl Neurodegener 13: 28. https://doi.org/10.1186/s40035-024-00416-x
[24]	Mejzini R, Flynn LL, Pitout IL, et al. (2019) ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?. Front Neurosci 13: 1310. https://doi.org/10.3389/fnins.2019.01310
[25]	Chiò A, Calvo A, Mazzini L, et al. (2012) Extensive genetics of ALS: a population-based study in Italy. Neurology 79: 1983-1989. https://doi.org/10.1212/WNL.0b013e3182735d36
[26]	Ungaro C, Sprovieri T, Morello G, et al. (2021) Genetic investigation of amyotrophic lateral sclerosis patients in south Italy: a two-decade analysis. Neurobiol Aging 99: 99.e7-99.e14. https://doi.org/10.1016/j.neurobiolaging.2020.08.017
[27]	Chen S, Sayana P, Zhang X, et al. (2013) Genetics of amyotrophic lateral sclerosis: an update. Mol Neurodegener 8: 28. https://doi.org/10.1186/1750-1326-8-28
[28]	de Jong SW, Huisman MH, Sutedja NA, et al. (2012) Smoking, alcohol consumption, and the risk of amyotrophic lateral sclerosis: a population-based study. Am J Epidemiol 176: 233-239. https://doi.org/10.1093/aje/kws015
[29]	Chapman L, Cooper-Knock J, Shaw PJ (2023) Physical activity as an exogenous risk factor for amyotrophic lateral sclerosis: a review of the evidence. Brain 146: 1745-1757. https://doi.org/10.1093/brain/awac470
[30]	McKay KA, Smith KA, Smertinaite L, et al. (2021) Military service and related risk factors for amyotrophic lateral sclerosis. Acta Neurol Scand 143: 39-50. https://doi.org/10.1111/ane.13345
[31]	Trojsi F, Monsurrò MR, Tedeschi G (2013) Exposure to environmental toxicants and pathogenesis of amyotrophic lateral sclerosis: state of the art and research perspectives. Int J Mol Sci 14: 15286-311. https://doi.org/10.3390/ijms140815286
[32]	Huss A, Spoerri A, Egger M, et al. (2015) Occupational exposure to magnetic fields and electric shocks and risk of ALS: the Swiss National Cohort. Amyotroph Lateral Scler Frontotemporal Degener 16: 80-85. https://doi.org/10.3109/21678421.2014.954588
[33]	Masrori P, Van Damme P (2020) Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol 27: 1918-1929. https://doi.org/10.1111/ene.14393
[34]	Milella G, Zoccolella S, Urso D, et al. (2023) Different patterns of spreading direction and motor neurons involvement in a cohort of limb-onset amyotrophic lateral sclerosis patients from Southern Italy: Potential implication on disease course or progression?. Brain Behav 13: e2899. https://doi.org/10.1002/brb3.2899
[35]	Liewluck T, Saperstein DS (2015) Progressive Muscular Atrophy. Neurol Clin 33: 761-773. https://doi.org/10.1016/j.ncl.2015.07.005
[36]	Vacchiano V, Bonan L, Liguori R, et al. (2024) Primary Lateral Sclerosis: An Overview. J Clin Med 13: 578. https://doi.org/10.3390/jcm13020578
[37]	Simonds AK (2017) Progress in respiratory management of bulbar complications of motor neuron disease/amyotrophic lateral sclerosis?. Thorax 72: 199-201. https://doi.org/10.1136/thoraxjnl-2016-208919
[38]	Kupelian V, Viscidi E, Hall S, et al. (2023) Increased Risk of Venous Thromboembolism in Patients With Amyotrophic Lateral Sclerosis: Results From a US Insurance Claims Database Study. Neurol Clin Pract 13: e200110. https://doi.org/10.1212/CPJ.0000000000200110
[39]	de Carvalho M (2020) Electrodiagnosis of Amyotrophic Lateral Sclerosis: A Review of Existing Guidelines. J Clin Neurophysiol 37: 294-298. https://doi.org/10.1097/WNP.0000000000000682
[40]	Verma A (2021) Clinical Manifestation and Management of Amyotrophic Lateral Sclerosis. Amyotrophic Lateral Sclerosis [Internet] . Brisbane (AU): Exon Publications 1-14. https://doi.org/10.36255/exonpublications.amyotrophiclateralsclerosis.management.2021
[41]	Oskarsson B, Gendron TF, Staff NP (2018) Amyotrophic Lateral Sclerosis: An Update for 2018. Mayo Clin Proc 93: 1617-1628. https://doi.org/10.1016/j.mayocp.2018.04.007
[42]	Liu J, Zhang X, Ding X, et al. (2019) Analysis of clinical and electrophysiological characteristics of 150 patients with amyotrophic lateral sclerosis in China. Neurol Sci 40: 363-369. https://doi.org/10.1007/s10072-018-3633-6
[43]	Arachchige ASPM (2023) Transitioning from PET/MR to trimodal neuroimaging: why not cover the temporal dimension with EEG?. AIMS Neurosci 10: 1-4. https://doi.org/10.3934/Neuroscience.2023001
[44]	Arachchige ASPM, Garner AK (2023) Seven Tesla MRI in Alzheimer's disease research: State of the art and future directions: A narrative review. AIMS Neurosci 10: 401-422. https://doi.org/10.3934/Neuroscience.2023030
[45]	Souza PV, Pinto WB, Oliveira AS (2014) Bright tongue sign: a diagnostic marker for amyotrophic lateral sclerosis. Arq Neuropsiquiatr 72: 572. https://doi.org/10.1590/0004-282X20140077
[46]	Valaparla VL, Lobaina M, Patel C, et al. (2023) Motor Band Sign in Primary Lateral Sclerosis: A Case Report Proposing the Need for an Imaging Biomarker. Cureus 15: e36121. https://doi.org/10.7759/cureus.36121
[47]	Braun N, Macklin EA, Sinani E, et al. (2020) Pooled Resource Open-Access ALS Clinical Trials Consortium. The revised El Escorial criteria “clinically probable laboratory supported ALS”-once a promising now a superfluous category?. Amyotroph Lateral Scler Frontotemporal Degener 21: 24-28. https://doi.org/10.1080/21678421.2019.1666875
[48]	Finsterer J, Stöllberger C (2013) Apply Awaji-shima Consensus Conference Criteria Before Diagnosing Amyotrophic Lateral Sclerosis. Open Neurol J 7: 4-6. https://doi.org/10.2174/1874205X01307010004
[49]	Feldman EL, Goutman SA, Petri S, et al. (2022) Amyotrophic lateral sclerosis. Lancet 400: 1363-1380. https://doi.org/10.1016/S0140-6736(22)01272-7
[50]	Miller TM, Cudkowicz ME, Genge A, et al. (2022) Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med 387: 1099-1110. https://doi.org/10.1056/NEJMoa2204705
[51]	Paganoni S, Hendrix S, Dickson SP, et al. (2021) Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis. Muscle Nerve 63: 31-39. https://doi.org/10.1002/mus.27091
[52]	Cruz MP (2018) Edaravone (Radicava): A Novel Neuroprotective Agent for the Treatment of Amyotrophic Lateral Sclerosis. P T 43: 25-28.
[53]	Saitoh Y, Takahashi Y (2020) Riluzole for the treatment of amyotrophic lateral sclerosis. Neurodegener Dis Manag 10: 343-355. https://doi.org/10.2217/nmt-2020-0033
[54]	Colombo G, Artico R, Barbareschi D (2020) Riluzole Oral Suspension for the Treatment of Amyotrophic Lateral Sclerosis: Texture and Compatibility with Food Thickeners Evaluation. J 3: 275-288. https://doi.org/10.3390/j3030021
[55]	Wymer J, Apple S, Harrison A, et al. (2023) Pharmacokinetics, Bioavailability, and Swallowing Safety With Riluzole Oral Film. Clin Pharmacol Drug Dev 12: 57-64. https://doi.org/10.1002/cpdd.1168
[56]	Cruz MP (2013) Nuedexta for the treatment of pseudobulbar affect: a condition of involuntary crying or laughing. P T 38: 325-328.
[57]	Burkhardt C, Neuwirth C, Sommacal A, et al. (2017) Is survival improved by the use of NIV and PEG in amyotrophic lateral sclerosis (ALS)? A post-mortem study of 80 ALS patients. PLoS One 12: e0177555. https://doi.org/10.1371/journal.pone.0177555
[58]	Jost WH, Bäumer T, Laskawi R, et al. (2019) Therapy of Sialorrhea with Botulinum Neurotoxin. Neurol Ther 8: 273-288. https://doi.org/10.1007/s40120-019-00155-6
[59]	Slade A, Stanic S (2015) Managing excessive saliva with salivary gland irradiation in patients with amyotrophic lateral sclerosis. J Neurol Sci 352: 34-36. https://doi.org/10.1016/j.jns.2015.02.008
[60]	Meglio M (2023) ALS Candidate PrimeC Meets Primary Safety and Secondary End Points in Phase 2b PARADIGM Study. Neurol Live .
[61]	Singh S, Kerndt CC, Chauhan S, et al. (2023) Mexiletine. StatPearls, Treasure Island (FL): StatPearls Publishing.
[62]	Oskarsson B, Moore D, Mozaffar T, et al. (2018) Mexiletine for muscle cramps in amyotrophic lateral sclerosis: A randomized, double-blind crossover trial. Muscle Nerve 58: 42-48. https://doi.org/10.1002/mus.26117
[63]	Naia L, Ly P, Mota SI, et al. (2021) The Sigma-1 Receptor Mediates Pridopidine Rescue of Mitochondrial Function in Huntington Disease Models. Neurotherapeutics 18: 1017-1038. https://doi.org/10.1007/s13311-021-01022-9
[64]	Berry JD, Cudkowicz ME, Windebank AJ, et al. (2019) NurOwn, phase 2, randomized, clinical trial in patients with ALS: Safety, clinical, and biomarker results. Neurology 93: e2294-e2305. https://doi.org/10.1212/WNL.0000000000008620
[65]	Cudkowicz ME, Lindborg SR, Goyal NA, et al. (2022) A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis. Muscle Nerve 65: 291-302. https://doi.org/10.1002/mus.27472
[66]	Onders RP, Carlin AM, Elmo M, et al. (2009) Amyotrophic lateral sclerosis: the Midwestern surgical experience with the diaphragm pacing stimulation system shows that general anesthesia can be safely performed. Am J Surg 197: 386-390. https://doi.org/10.1016/j.amjsurg.2008.11.008
[67]	Dorst J, Ludolph AC, Huebers A (2017) Disease-modifying and symptomatic treatment of amyotrophic lateral sclerosis. Ther Adv Neurol Disord 11: 1756285617734734. https://doi.org/10.1177/1756285617734734
[68]	Spittel S, Maier A, Kettemann D, et al. (2021) Non-invasive and tracheostomy invasive ventilation in amyotrophic lateral sclerosis: Utilization and survival rates in a cohort study over 12 years in Germany. Eur J Neurol 28: 1160-1171. https://doi.org/10.1111/ene.14647
[69]	Kim EY, Kang SW, Suh MR, et al. (2021) Safety of Gastrostomy Tube Placement in Patients with Advanced Amyotrophic Lateral Sclerosis With Noninvasive Ventilation. JPEN J Parenter Enteral Nutr 45: 1338-1346. https://doi.org/10.1002/jpen.2018
[70]	Andersen PM, Abrahams S, et al. (2012) EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)--revised report of an EFNS task force. Eur J Neurol 19: 360-375. https://doi.org/10.1111/j.1468-1331.2011.03501.x
[71]	Miller RG, Jackson CE, Kasarskis EJ, et al. (2009) Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 73: 1227-1233. https://doi.org/10.1212/WNL.0b013e3181bc01a4
[72]	J Paul D, Wright M, M Palmer J, et al. (2022) Perioperative management of patients with amyotrophic lateral sclerosis: A narrative review. Anaesth Intensive Care 50: 345-360. https://doi.org/10.1177/0310057X211065042
[73]	Arachchige ASPM (2023) Neuroimaging with PET/MR: moving beyond 3 T in preclinical systems, when for clinical practice?. Clin Transl Imaging 11: 315-319. https://doi.org/10.1007/s40336-023-00572-6
[74]	Arachchige ASPM (2023) Neuroimaging with SPECT-MRI: a myth or reality?. AIMS Neurosci 10: 52-55. https://doi.org/10.3934/Neuroscience.2023004
[75]	Verma Y, Ramesh S, Perera Molligoda Arachchige AS (2024) 7 T Versus 3 T in the Diagnosis of Small Unruptured Intracranial Aneurysms: Reply to Radojewski et al. Clin Neuroradiol 34: 51-52. https://doi.org/10.1007/s00062-023-01321-y

Reader Comments

Your name:*

Email:*
© 2025 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)