Abstract

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive loss of motor neurons. While the late-stage pathology is well-documented, the initial, pre-symptomatic cellular dysfunctions that trigger disease onset remain a critical area of investigation. This review focuses on the earliest pathogenetic mechanisms, particularly those involving cellular membranes and organelles, which are increasingly recognized as central to disease initiation. We synthesize evidence highlighting early alterations in the integrity and function of the plasma membrane, endoplasmic reticulum (ER), and mitochondria-associated membranes (MAMs). These membrane dysfunctions are linked to impaired calcium homeostasis, aberrant protein aggregation (such as TDP-43 and SOD1), and mitochondrial bioenergetic failure, collectively compromising neuronal health before clinical symptoms emerge. The paper discusses how these early membrane-centric defects, including altered lipid rafts and impaired nucleocytoplasmic transport, establish a toxic cellular environment. Understanding these initial dysfunctions provides crucial insight into the fundamental mechanisms of ALS pathogenesis and identifies novel, early-stage therapeutic targets aimed at preventing or significantly delaying disease progression.