{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T23:59:15Z","timestamp":1785542355465,"version":"3.56.0"},"reference-count":84,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:00:00Z","timestamp":1729209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Florence (Fondi di Ateneo)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Proteinopathies involve the abnormal accumulation of specific proteins. Maintaining the balance of the proteome is a finely regulated process managed by a complex network of cellular machinery responsible for protein synthesis, folding, and degradation. However, stress and ageing can disrupt this balance, leading to widespread protein aggregation. Currently, several therapies targeting protein aggregation are in clinical trials for ALS. These approaches mainly focus on two strategies: addressing proteins that are prone to aggregation due to mutations and targeting the cellular mechanisms that maintain protein homeostasis to prevent aggregation. This review will cover these emerging drugs. Advances in ALS research not only offer hope for better outcomes for ALS patients but also provide valuable insights and methodologies that can benefit the broader field of neurodegenerative disease drug discovery.<\/jats:p>","DOI":"10.3390\/biom14101324","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T05:03:49Z","timestamp":1729227829000},"page":"1324","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Targeting Protein Aggregation in ALS"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7593-8376","authenticated-orcid":false,"given":"Michele","family":"Perni","sequence":"first","affiliation":[{"name":"Baz-Therapeutics Inc., 810 Rittenhouse Square, Suite 412, Philadelphia, PA 19103, USA"},{"name":"Clinical Research Building, Perelman School of Medicine, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6812-7348","authenticated-orcid":false,"given":"Benedetta","family":"Mannini","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences Mario Serio, University of Florence, Viale Morgagni 50, 50134 Florence, Italy"},{"name":"Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.semcdb.2018.05.003","article-title":"Protein Aggregation in Cell Biology: An Aggregomics Perspective of Health and Disease","volume":"99","author":"Cox","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/nature10317","article-title":"Molecular Chaperones in Protein Folding and Proteostasis","volume":"475","author":"Hartl","year":"2011","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1073\/pnas.1910444117","article-title":"Proteome-Wide Observation of the Phenomenon of Life on the Edge of Solubility","volume":"117","author":"Vecchi","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1073\/pnas.1912897117","article-title":"Widespread Remodeling of Proteome Solubility in Response to Different Protein Homeostasis Stresses","volume":"117","author":"Sui","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/j.cell.2015.03.032","article-title":"Widespread Proteome Remodeling and Aggregation in Aging C. Elegans","volume":"161","author":"Walther","year":"2015","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1146\/annurev-biochem-060614-033955","article-title":"The Biology of Proteostasis in Aging and Disease","volume":"84","author":"Labbadia","year":"2015","journal-title":"Annu. Rev. Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1126\/science.1141448","article-title":"Adapting Proteostasis for Disease Intervention","volume":"319","author":"Balch","year":"2008","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.tcb.2018.02.004","article-title":"Protein Phase Separation: A New Phase in Cell Biology","volume":"28","author":"Boeynaems","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1016\/j.cell.2013.05.037","article-title":"Eukaryotic Stress Granules Are Cleared by Autophagy and Cdc48\/VCP Function","volume":"153","author":"Buchan","year":"2013","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.cell.2011.07.030","article-title":"Autophagy and Aging","volume":"146","author":"Rubinsztein","year":"2011","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.15252\/embj.201695957","article-title":"An Aberrant Phase Transition of Stress Granules Triggered by Misfolded Protein and Prevented by Chaperone Function","volume":"36","author":"Mateju","year":"2017","journal-title":"EMBO J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"fcab148","DOI":"10.1093\/braincomms\/fcab148","article-title":"Analysis of Circulating Protein Aggregates as a Route of Investigation into Neurodegenerative Disorders","volume":"3","author":"Adiutori","year":"2021","journal-title":"Brain Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s40035-024-00405-0","article-title":"Putative Novel CSF Biomarkers of Alzheimer\u2019s Disease Based on the Novel Concept of Generic Protein Misfolding and Proteotoxicity: The PRAMA Cohort","volume":"13","author":"Bigi","year":"2024","journal-title":"Transl. Neurodegener."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"eadg7162","DOI":"10.1126\/scitranslmed.adg7162","article-title":"Mis-Spliced Transcripts Generate de Novo Proteins in TDP-43-Related ALS\/FTD","volume":"16","author":"Seddighi","year":"2024","journal-title":"Sci. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/j.immuni.2024.03.010","article-title":"Innate Immune Activation in Neurodegenerative Diseases","volume":"57","author":"Heneka","year":"2024","journal-title":"Immunity"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e23068","DOI":"10.1096\/fj.202300573R","article-title":"Therapy of Autoimmune Inflammation in Sporadic Amyotrophic Lateral Sclerosis: Dimethyl Fumarate and H-151 Downregulate Inflammatory Cytokines in the cGAS-STING Pathway","volume":"37","author":"Zamiri","year":"2023","journal-title":"FASEB J."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kumar, S., Thangakani, A.M., Nagarajan, R., Singh, S.K., Velmurugan, D., and Gromiha, M.M. (2016). Autoimmune Responses to Soluble Aggregates of Amyloidogenic Proteins Involved in Neurodegenerative Diseases: Overlapping Aggregation Prone and Autoimmunogenic Regions. Sci. Rep., 6.","DOI":"10.1038\/srep22258"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1056\/NEJMoa2212948","article-title":"Lecanemab in Early Alzheimer\u2019s Disease","volume":"388","author":"Swanson","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1001\/jama.2023.13239","article-title":"Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial","volume":"330","author":"Sims","year":"2023","journal-title":"JAMA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"221","DOI":"10.3233\/JAD-2005-7304","article-title":"Ineffective Phagocytosis of Amyloid-\u03b2 by Macrophages of Alzheimer\u2019s Disease Patients","volume":"7","author":"Fiala","year":"2005","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1096\/fj.201601184","article-title":"Intraneuronal Protein Aggregation as a Trigger for Inflammation and Neurodegeneration in the Aging Brain","volume":"31","author":"Currais","year":"2017","journal-title":"FASEB J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1007\/s00401-013-1125-6","article-title":"Protein Aggregation in Amyotrophic Lateral Sclerosis","volume":"125","author":"Blokhuis","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/362059a0","article-title":"Mutations in Cu\/Zn Superoxide Dismutase Gene Are Associated with Familial Amyotrophic Lateral Sclerosis","volume":"362","author":"Rosen","year":"1993","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1177\/1073858414561795","article-title":"SOD1 Function and Its Implications for Amyotrophic Lateral Sclerosis Pathology: New and Renascent Themes","volume":"21","author":"Saccon","year":"2015","journal-title":"Neuroscientist"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3491","DOI":"10.1038\/s41467-022-31240-4","article-title":"Cryo-EM Structure of an Amyloid Fibril Formed by Full-Length Human SOD1 Reveals Its Conformational Conversion","volume":"13","author":"Wang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/S1474-4422(08)70071-1","article-title":"TARDBP Mutations in Amyotrophic Lateral Sclerosis with TDP-43 Neuropathology: A Genetic and Histopathological Analysis","volume":"7","author":"Leverenz","year":"2008","journal-title":"Lancet Neurol."},{"key":"ref_27","first-page":"E1121","article-title":"Partial Loss of TDP-43 Function Causes Phenotypes of Amyotrophic Lateral Sclerosis","volume":"111","author":"Yang","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1038\/s41586-023-06405-w","article-title":"TDP-43 Forms Amyloid Filaments with a Distinct Fold in Type A FTLD-TDP","volume":"620","author":"Arseni","year":"2023","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/s41586-021-04199-3","article-title":"Structure of Pathological TDP-43 Filaments from ALS with FTLD","volume":"601","author":"Arseni","year":"2022","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"R46","DOI":"10.1093\/hmg\/ddq137","article-title":"TDP-43 and FUS\/TLS: Emerging Roles in RNA Processing and Neurodegeneration","volume":"19","author":"Polymenidou","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1093\/jnen\/nlaa003","article-title":"Characteristic Features of FUS Inclusions in Spinal Motor Neurons of Sporadic Amyotrophic Lateral Sclerosis","volume":"79","author":"Ikenaka","year":"2020","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"103701","DOI":"10.1016\/j.isci.2021.103701","article-title":"Molecular Structure of an Amyloid Fibril Formed by FUS Low-Complexity Domain","volume":"25","author":"Sun","year":"2022","journal-title":"iScience"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.neuron.2011.09.010","article-title":"A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD","volume":"72","author":"Renton","year":"2011","journal-title":"Neuron"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.ajhg.2013.01.011","article-title":"Large C9orf72 Hexanucleotide Repeat Expansions Are Seen in Multiple Neurodegenerative Syndromes and Are More Frequent than Expected in the UK Population","volume":"92","author":"Beck","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1126\/science.1232927","article-title":"The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD\/ALS","volume":"339","author":"Mori","year":"2013","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Petrauskas, A., Fortunati, D.L., Kandi, A.R., Pothapragada, S.S., Agrawal, K., Singh, A., Huelsmeier, J., Hillebrand, J., Brown, G., and Chaturvedi, D. (2024). Structured and Disordered Regions of Ataxin-2 Contribute Differently to the Specificity and Efficiency of mRNP Granule Formation. PLoS Genet., 20.","DOI":"10.1371\/journal.pgen.1011251"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1083\/jcb.201302044","article-title":"Stress Granules as Crucibles of ALS Pathogenesis","volume":"201","author":"Li","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1038\/nature09320","article-title":"Ataxin-2 Intermediate-Length Polyglutamine Expansions Are Associated with Increased Risk for ALS","volume":"466","author":"Elden","year":"2010","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/nature22038","article-title":"Therapeutic Reduction of Ataxin-2 Extends Lifespan and Reduces Pathology in TDP-43 Mice","volume":"544","author":"Becker","year":"2017","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s41392-023-01486-5","article-title":"Role of Neuroinflammation in Neurodegeneration Development","volume":"8","author":"Zhang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1056\/NEJMoa2003715","article-title":"Phase 1\u20132 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS","volume":"383","author":"Miller","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1056\/NEJMoa2204705","article-title":"Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS","volume":"387","author":"Miller","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4484","DOI":"10.1212\/WNL.96.15_supplement.4484","article-title":"A Phase 1, Multicenter, Open Label, Single-Ascending Dose Study to Evaluate Safety, Tolerability, and Pharmacokinetics of AP-101 in Familial and Sporadic Amyotrophic Lateral Sclerosis (ALS) (4484)","volume":"96","author":"Genge","year":"2021","journal-title":"Neurology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/s41591-021-01615-z","article-title":"Antisense Oligonucleotide Silencing of FUS Expression as a Therapeutic Approach in Amyotrophic Lateral Sclerosis","volume":"28","author":"Korobeynikov","year":"2022","journal-title":"Nat. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e028486","DOI":"10.1136\/bmjopen-2018-028486","article-title":"Proteostasis and ALS: Protocol for a Phase II, Randomised, Double-Blind, Placebo-Controlled, Multicentre Clinical Trial for Colchicine in ALS (Co-ALS)","volume":"9","author":"Mandrioli","year":"2019","journal-title":"BMJ Open"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"fcae304","DOI":"10.1093\/braincomms\/fcae304","article-title":"Colchicine Treatment in Amyotrophic Lateral Sclerosis: Safety, Biological and Clinical Effects in a Randomized Clinical Trial","volume":"6","author":"Gianferrari","year":"2024","journal-title":"Brain Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.1093\/brain\/awab167","article-title":"The Unfolded Protein Response in Amyotrophic Later Sclerosis: Results of a Phase 2 Trial","volume":"144","author":"Bella","year":"2021","journal-title":"Brain"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e015434","DOI":"10.1136\/bmjopen-2016-015434","article-title":"Protein Misfolding, Amyotrophic Lateral Sclerosis and Guanabenz: Protocol for a Phase II RCT with Futility Design (ProMISe Trial)","volume":"7","author":"Tramacere","year":"2017","journal-title":"BMJ Open"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3555","DOI":"10.1212\/WNL.0000000000203354","article-title":"The Integrated Stress Response Is Modulated by eIF2B Agonist DNL343: Results From Phase 1 Healthy Subject and Phase 1b ALS Patient Studies. (P8-8.010)","volume":"100","author":"Sun","year":"2023","journal-title":"Neurology"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Yulyaningsih, E., Suh, J.H., Fanok, M.H., Chau, R., Solanoy, H., Takahashi, R., Bakardjiev, A.I., Becerra, I., Benitez, N.B., and Chiu, C.-L. (2024). DNL343 Is an Investigational CNS Penetrant eIF2B Activator That Prevents and Reverses the Effects of Neurodegeneration Caused by the Integrated Stress Response. bioRxiv.","DOI":"10.7554\/eLife.92173.2.sa4"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4188","DOI":"10.1212\/WNL.0000000000203810","article-title":"A Phase 1 First-in-Human Study to Investigate the Safety, Tolerability and Food Effect of ABBV-CLS-7262 (P6-4.002)","volume":"100","author":"Cho","year":"2023","journal-title":"Neurology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/S1474-4422(24)00216-3","article-title":"Safety, Tolerability, and Pharmacokinetics of Antisense Oligonucleotide BIIB078 in Adults with C9orf72-Associated Amyotrophic Lateral Sclerosis: A Phase 1, Randomised, Double Blinded, Placebo-Controlled, Multiple Ascending Dose Study","volume":"23","author":"Rothstein","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/S1474-4422(24)00134-0","article-title":"Safety and Efficacy of Arimoclomol in Patients with Early Amyotrophic Lateral Sclerosis (ORARIALS-01): A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase 3 Trial","volume":"23","author":"Benatar","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1007\/s13311-022-01237-4","article-title":"Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: The ATLAS Study","volume":"19","author":"Benatar","year":"2022","journal-title":"Neurotherapeutics"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1111\/bph.15148","article-title":"Targeting TDP-43 Proteinopathy with Drugs and Drug-like Small Molecules","volume":"178","author":"Buratti","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3908","DOI":"10.1093\/hmg\/ddw232","article-title":"The Chaperone HSPB8 Reduces the Accumulation of Truncated TDP-43 Species in Cells and Protects against TDP-43-Mediated Toxicity","volume":"25","author":"Crippa","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Crippa, V., D\u2019Agostino, V.G., Cristofani, R., Rusmini, P., Cicardi, M.E., Messi, E., Loffredo, R., Pancher, M., Piccolella, M., and Galbiati, M. (2016). Transcriptional Induction of the Heat Shock Protein B8 Mediates the Clearance of Misfolded Proteins Responsible for Motor Neuron Diseases. Sci. Rep., 6.","DOI":"10.1038\/srep22827"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Alberti, S., Mateju, D., Mediani, L., and Carra, S. (2017). Granulostasis: Protein Quality Control of RNP Granules. Front. Mol. Neurosci., 10.","DOI":"10.3389\/fnmol.2017.00084"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"212","DOI":"10.2165\/00003495-198326030-00003","article-title":"Guanabenz: A Review of Its Pharmacodynamic Properties and Therapeutic Efficacy in Hypertension","volume":"26","author":"Holmes","year":"1983","journal-title":"Drugs"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1126\/science.1201396","article-title":"Selective Inhibition of a Regulatory Subunit of Protein Phosphatase 1 Restores Proteostasis","volume":"332","author":"Tsaytler","year":"2011","journal-title":"Science"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"eaat5314","DOI":"10.1126\/science.aat5314","article-title":"The Integrated Stress Response: From Mechanism to Disease","volume":"368","author":"Walter","year":"2020","journal-title":"Science"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S1474-4422(06)70440-9","article-title":"Vanishing White Matter Disease","volume":"5","author":"Pronk","year":"2006","journal-title":"Lancet Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1093\/brain\/aww101","article-title":"The Unfolded Protein Response: Mechanisms and Therapy of Neurodegeneration","volume":"139","author":"Smith","year":"2016","journal-title":"Brain"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5758","DOI":"10.1021\/acs.jmedchem.3c02422","article-title":"Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases","volume":"67","author":"Craig","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Marlin, E., Viu-Idocin, C., Arrasate, M., and Arag\u00f3n, T. (2022). The Role and Therapeutic Potential of the Integrated Stress Response in Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147823"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/s41419-020-2601-2","article-title":"Fine Tuning of the Unfolded Protein Response by ISRIB Improves Neuronal Survival in a Model of Amyotrophic Lateral Sclerosis","volume":"11","author":"Bugallo","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"18591","DOI":"10.1073\/pnas.2005748117","article-title":"Metformin Inhibits RAN Translation through PKR Pathway and Mitigates Disease in C9orf72 ALS\/FTD Mice","volume":"117","author":"Zu","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1007\/s12325-018-0694-0","article-title":"Combination Glucose-Lowering Therapy Plans in T2DM: Case-Based Considerations","volume":"35","author":"Blonde","year":"2018","journal-title":"Adv. Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1073\/pnas.1013343108","article-title":"Non-ATG-Initiated Translation Directed by Microsatellite Expansions","volume":"108","author":"Zu","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1517\/17425255.4.8.1119","article-title":"Ambroxol in the 21st Century: Pharmacological and Clinical Update","volume":"4","author":"Malerba","year":"2008","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"23502","DOI":"10.1074\/jbc.M109.012393","article-title":"Identification and Characterization of Ambroxol as an Enzyme Enhancement Agent for Gaucher Disease","volume":"284","author":"Maegawa","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1093\/hmg\/ddi240","article-title":"ER Retention and Degradation as the Molecular Basis Underlying Gaucher Disease Heterogeneity","volume":"14","author":"Ron","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3306","DOI":"10.1523\/JNEUROSCI.5367-11.2012","article-title":"Endoplasmic Reticulum Stress Is Important for the Manifestations of \u03b1-Synucleinopathy In Vivo","volume":"32","author":"Colla","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Bouscary, A., Quessada, C., Mosbach, A., Callizot, N., Spedding, M., Loeffler, J.-P., and Henriques, A. (2019). Ambroxol Hydrochloride Improves Motor Functions and Extends Survival in a Mouse Model of Familial Amyotrophic Lateral Sclerosis. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.00883"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.omtn.2022.04.007","article-title":"Preclinical Evaluation of WVE-004, Aninvestigational Stereopure Oligonucleotide Forthe Treatment of C9orf72-Associated ALS or FTD","volume":"28","author":"Liu","year":"2022","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"208ra149","DOI":"10.1126\/scitranslmed.3007529","article-title":"Targeting RNA Foci in iPSC-Derived Motor Neurons from ALS Patients with a C9ORF72 Repeat Expansion","volume":"5","author":"Sareen","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.neuron.2016.04.006","article-title":"Gain of Toxicity from ALS\/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs","volume":"90","author":"Jiang","year":"2016","journal-title":"Neuron"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Mejzini, R., Flynn, L.L., Pitout, I.L., Fletcher, S., Wilton, S.D., and Akkari, P.A. (2019). ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.01310"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Keon, M., Musrie, B., Dinger, M., Brennan, S.E., Santos, J., and Saksena, N.K. (2021). Destination Amyotrophic Lateral Sclerosis. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.596006"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1001\/jamaneurol.2019.1971","article-title":"Prevalence of Biologically vs Clinically Defined Alzheimer Spectrum Entities Using the National Institute on Aging\u2014Alzheimer\u2019s Association Research Framework","volume":"76","author":"Jack","year":"2019","journal-title":"JAMA Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13195-016-0207-9","article-title":"Drug Development in Alzheimer\u2019s Disease: The Path to 2025","volume":"8","author":"Cummings","year":"2016","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.stem.2022.01.007","article-title":"iPSC-Based Disease Modeling and Drug Discovery in Cardinal Neurodegenerative Disorders","volume":"29","author":"Okano","year":"2022","journal-title":"Cell Stem Cell"},{"key":"ref_83","unstructured":"Paul, M. (2024, August 22). In the senate of the United States. 117TH CONGRESS 2D SESSION. S.5002 Bill\u2013FDA Modernization Act 2.0. 2022, 1\u20133, Available online: https:\/\/www.congress.gov\/bill\/117th-congress\/senate-bill\/5002."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e175824","DOI":"10.1172\/JCI175824","article-title":"FDA Modernization Act 2.0: Transitioning beyond Animal Models with Human Cells, Organoids, and AI\/ML-Based Approaches","volume":"133","author":"Zushin","year":"2023","journal-title":"J. Clin. Investig."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/10\/1324\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:15:51Z","timestamp":1760112951000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/10\/1324"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,18]]},"references-count":84,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["biom14101324"],"URL":"https:\/\/doi.org\/10.3390\/biom14101324","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,18]]}}}