Study provides first definitive evidence and description of protein clump toxicity in ALS.

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. This fatal disease is characterized by progressive muscular atrophy and doesn’t have an effective treatment.  Patients with ALS suffer gradual paralysis and early death as a result of the loss of motor neurons, which are crucial to moving, speaking, swallowing, and breathing.  Although a small proportion of ALS cases have a familiar origin, the vast majority of them are thought to be sporadic.

Since the linking of mutations in the Cu,Zn superoxide dismutase gene (SOD1) to ALS in 1993, researchers have sought the connection between SOD1 and motor neuron death.  Now, a study from researchers at the University of North Carolina provides the first-ever evidence-based description of the neuronal protein clumps thought to be important in ALS.  The team state that their findings also provide the first definitive evidence that these protein clumps are indeed toxic to the type of neurons that die in patients with ALS.  The study is published in the journal Proceedings of the National Academy of Sciences.

Previous studies show ALS is a neurodegenerative disease characterized by the development of voluntary muscle paralysis that usually begins focally. This disease eventually leads to death, usually within 2~3 years of symptom onset. Important pathological features of ALS include the selective neuronal loss of lower motor neurons in the spinal cord and upper motor neurons in the brain in the absence of sensory symptoms. A subset of ALS cases have genetic causes, whereas over 90% of all ALS cases are sporadic.  Disease-linked mutations tend to destabilize the native dimeric structure of SOD1, and plaques containing misfolded and aggregated SOD1 have been found in the motor neurons of patients with ALS. Despite advances in understanding of ALS disease progression and SOD1 folding and stability, cytotoxic species and mechanisms remain unknown, greatly impeding the search for and design of therapeutic interventions.  The current study shows that the protein forms temporary clumps of three, known as a ‘trimer,’ and that these clumps are capable of killing motor neuron-like cells grown in the laboratory.

The current study focused on a subset of ALS cases, an estimated 1 to 2%, that are associated with variations in a protein known as SOD1. The lab note that even in patients without mutations in their SOD1 gene, this protein has been shown to form potentially toxic clumps. Once the trimers’ structure was established, the team spent several more years developing methods to test the trimers’ effects on motor neuron-like cells grown in the laboratory. Results show that SOD1 proteins that were tightly bound into trimers were lethal to the motor neuron-like cells, while non-clumped SOD1 proteins were not.

The group used a combination of computational modeling and experiments in live cells and spent two years developing a custom algorithm to determine the trimers’ structure.  The team state that, to their knowledge, it was not known exactly what toxic interactions were behind the death of motor neurons in patients with ALS.  They go on to add that knowing what these trimers look like, the global medical community can now use this knowledge to better attempt to design drugs that would stop them from forming.

The team surmise that their study is a big breakthrough as it sheds light on the origin of motor neuron death and could be very important for drug discovery.  For the future, the researchers plan to investigate the glue that holds the trimers together in order to find drugs that could break them apart or keep them from forming.  They go on to conclude that these findings could help shed light on other neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s.

Source: University of North Carolina at Chapel Hill School of Medicine