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Patients with amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and other neurodegenerative disorders typically start to display clinical symptoms during adulthood. Groundbreaking genetic studies in humans, rodents, Caenorhabditis elegans, Drosophila, and yeast have identified mutations in genes such as SOD1, FUS/TLS and TDP-43 (for ALS), APP and presenilin (for AD), parkin and alpha-synuclein (for PD), and huntingtin (for HD), as being responsible for causing these diseases in adults, even though the mutation is present throughout life. Despite remarkable advances in understanding the diseases, no mechanism-based cures are currently available. This unfortunate situation is mainly due to the fact that the primary target(s) of the mutant proteins are not known, in part because early and ubiquitous expression of the aberrant genes in the developing CNS leads to many secondary effects and triggers compensatory mechanisms that mask the primary pathological event. Thus, although the primary disease process might be present throughout life, onset of symptoms coincides with the saturation of protection and compensation mechanisms, either by accumulation of dysfunction or via other pathogenic events such as trauma and environmental factors, which may be aggravated by aging [DeKosky and Marek, 2003; Palop et al., 2006]. To enable identification of mutant gene-driven mechanisms that trigger the cascade of events that culminate in degeneration and death later in life, a first step is to establish exactly when the neuropathology is initiated. The fact that the expression of the disease-causative proteins starts during embryonic stages raises the intriguing possibility that pathological changes in patients with adult-onset neurodegenerative disorders are triggered much earlier—in humans, such alterations may occur decades, and in mouse models months—prior to the manifestation of symptoms. Recent support for this contention derives from findings that alterations are found in many CNS regions in pre-symptomatic transgenic mouse models (and even in pre-symptomatic human patients) of ALS (see below), AD [Santos et al., 2010], PK [Obeso et al., 2010], and HD [Raymond et al., 2011]. Based on evidence that is discussed more fully below, we propose a model (Fig. 1) in which mutant SOD1 initiates synaptic pathogenesis very early in development, causing alterations in neural circuits and network activity, and resulting in a vicious cycle that leads to neurological impairment. The onset of symptoms of ALS in humans may take years and even decades following these early events, and may become apparent only when compensatory mechanisms breaks down. Thus, it is imperative that the primary target(s) of disease-causing proteins be identified, which can then be used to establish pre-symptomatic diagnostic tools, and to develop novel therapies that can effectively prevent the onset of irreversible neuronal damage. Fig. 1 Model of how mutant SOD1 may underlie the etiology of ALS. Subtle synaptic dysfunction may be initiated by mutant SOD1 during development: either at early postnatal stages, or even during embryogenesis, when expression of wild-type and mutant SOD1 is ...