Figure 1.

The pathology of ALS encompasses all levels of the voluntary neuromuscular system and involves multiple cell types. The primary targets of ALS are motor neurons in the cortex, brainstem, and spinal cord. Neuropathological characteristics of most ALS cases are TDP43 inclusions in both neurons and glial cells. Neuroinflammation is raging throughout the nervous system with activated microglia and astrocytes seen wherever degeneration is occurring. The loss of upper and lower motor neurons is further evident from axonal degeneration and demyelination of the corticospinal tract as well as of the peripheral spinal nerves innervating skeletal muscles [2,3]. Denervation of neuromuscular junctions on affected skeletal muscle fibers have begun prior to clinical onset of any apparent motor deficit. While FF motor axons retract and degenerate, S motor neurons sprout and innervate endplates vacated by FF motor neurons. This new innervation results in fiber type switching and apparent grouping of muscle fiber types followed by atrophy of permanently denervated muscle fibers [4,5,6].