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Early misfolded superoxide dismutase 1 (mfSOD1) accumulation, motor neuron (MN) degeneration, and microgliosis are hallmark pathological features in SOD1G93A amyotrophic lateral sclerosis (ALS) mice. Because of the different vulnerabilities of distinct MN subtypes, degenerating and surviving MNs coexist in different proportions during disease progression. By examining the expression of misfolded conformers of SOD1 using specific antibodies, we defined distinct MN phenotypes that were evaluated during disease progression and the local neuroinflammatory reaction. The most severe phenotype corresponded to somata of fast‐twitch subtype MNs, which exhibited highly positive mfSOD1 immunostaining and an extreme degree of vacuolar degeneration. Vacuoles, which are of mitochondrial origin, contain mfSOD1 in conjunction with nonmitochondrial proteins, such as chromogranin, CD81, and flotillin. The fusion of ER‐derived vesicles enriched in mfSOD1 with outer mitochondrial membranes is thought to be the primary mechanism for vacuole formation. In addition, the ulterior coalescence of enlarged mitochondria may lead to the formation of giant vacuoles. Vacuolar degeneration is a transient degenerative process occurring early during the presymptomatic stages of the disease in ALS mice. Some vacuolated MNs are also positive for pMLKL, the effector protein of necroptosis. This indicates a newly described mechanism in which extracellular vesicles derived from damaged MNs, via cellular secretion or necroptotic disruption, may be the triggers for initiating neuroinflammation, glial‐mediated neurotoxicity, and disease spreading. Furthermore, as MN degeneration in mutant SOD1 mice is noncell autonomous, the effects of experimentally increasing or decreasing the microglial response on the expression of MN phenotypes were also evaluated, demonstrating bidirectional cross talk signaling between the degree of expression of mfSOD1 and local neuroinflammation. More detailed knowledge regarding these processes occurring long before the end stages of the disease is necessary to identify novel molecular targets for future preclinical testing. [ABSTRACT FROM AUTHOR]