What causes ALS?

The cause of ALS is largely unknown. Only about 5–10% of all people with ALS have a genetic mutation that can cause ALS or increase the risk of developing it. For the vast majority of those affected, the actual cause of the disease remains unclear. Even in the rare genetic form, it remains unclear why the mutations occur. In addition to the cause (“Why?”), the disease mechanism is also important (“What happens?”).

The mechanism of the disease is referred to as pathogenesis. Significant progress has been made in elucidating the pathogenesis. It has been known since the 1950s that certain protein deposits can be detected within motor neurons; these are referred to as “Bunin bodies”(named after their discoverer, a Russian neuropathologist). All ALS patients exhibit protein deposits in motor neurons as a pathological feature. For this reason, ALS is also considered a protein deposition disease (“proteinopathy”).

In 2006, it was discovered that in over 90% of all patients, the protein deposits (Bunina bodies) contain the protein TDP-43. It is important to note that protein deposits can also be detected in other neurodegenerative diseases (such as Alzheimer’s and Parkinson’s disease). What all neurodegenerative diseases have in common is that they are “proteinopathies”—however, the diseases differ in the location and composition of the protein deposits. It is considered likely that TDP-43 deposits contribute to damage to motor neurons. Future treatment strategies aim to prevent or reduce the accumulation of TDP-43 and other proteins.