2024/10/14 by Carmen Pérez de la Lastra, Carlota Tosat‐Bitrián, Gracia Porras +6 · 1 voice · 1 citation
Medicine · Neuroscience · #Amyotrophic Lateral Sclerosis Research #Genetic Neurodegenerative Diseases #Cholinesterase and Neurodegenerative Diseases
paper · doi:10.1021/acschemneuro.4c00328
openalex publication_date 2024/10/14 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/22
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that currently lacks effective therapy. Given the heterogeneity of clinical and molecular profiles of ALS patients, personalized diagnostics and pathological characterization represent a powerful strategy to optimize patient stratification, thereby enabling personalized treatment. Immortalized lymphocytes from sporadic and genetic ALS patients recapitulate some pathological hallmarks of the disease, facilitating the fundamental task of drug screening. However, the molecular aggregation of ALS has not been characterized in this patient-derived cellular model. Indeed, protein aggregation is one of the most prominent features of neurodegenerative diseases, and therefore, models to test drugs against personalized pathological aggregation could help discover improved therapies. With this work, we aimed to characterize the aggregation profile of ALS immortalized lymphocytes and test several drug candidates with different mechanisms of action. In addition, we have evaluated the molecular aggregation in motor neurons derived from two hiPSC cell lines corresponding to ALS patients with different mutations in TARDBP . The results provide valuable insight into the different characterization of sporadic and genetic ALS patients’ immortalized lymphocytes, their differential response to drug treatment, and the usefulness of proteome homeostasis characterization in patients’ cells.