Skeletal muscles are innervated by a group of neurones (lower motor neurones) located in the ventral horns of the spinal cord which project out the ventral roots to the muscle cells. These nerve cells are themselves innervated by thecorticospinal tract or upper motor neurones that project from the motor cortex of the brain. On macroscopic pathology, there is a degeneration of the ventral horns of the spinal cord, as well as atrophy of the ventral roots. In the brain, atrophy may be present in the frontal and temporal lobes. On microscopic examination, neurones may showspongiosis, the presence of astrocytes, and a number of inclusions including characteristic "skein-like" inclusions, Bunina bodies, and vacuolisation. Bunina bodies were first described in 1962; they are markers of neuronal degeneration.

The availability of mouse models has led to extensive research into the causes of SOD1-mutant linked familialALS. The most commonly used mouse model is G93A,[4]although many others have since been generated. At the gross physiological level, the mouse models faithfully recapitulate the features of human ALS (motorneuron death, muscle atrophy, respiratory failure).

Although there is no consensus as to the exact mechanism by which mutated SOD1 causes the disease (in either mice or patients), studies based largely on mouse models suggest a role for excitotoxicity and more controversially, oxidative stress, presumably secondary to mitochondrial dysfunction. Death by apoptosis has also been suggested.