The onset of ALS, also known as Lou Gehrig’s disease, is marked by the gradual degradation and eventual death of neuronal axons, the slender projections on nerve cells which transmit signals from one cell to the next. In approximately 95% of all ALS cases, the disease occurs apparently at random with no associated risk factors. Individuals with this sporadic form of the disease do not have a family history of ALS, and their family members are not considered to be at an increased risk for developing it. Now, a study from researchers at Harvard Medical School identifies a key instigator of nerve cell damage in people with ALS. The team state that their findings may lead to new therapies to halt the progression of this uniformly fatal disease which affects more than 30,000 Americans. The study is published in the journal Science.
Previous studies show the presence of optineurin protein producing gene defects in people with both inherited and sporadic forms of ALS, however, researchers were unsure how the optineurin gene was involved in the development of the disease. The current study shows that the aberrant behaviour of an enzyme called receptor-interacting kinase 1 (RIPK1), caused by a loss of the optineurin protein, damages neuronal axons by disrupting the production of myelin, the soft gel-like substance enveloping axons to insulate them from injury.
The current study utilises mice lacking the optineurin gene to show that this causes abnormally high levels of RIPK1, a known promoter of cell death and in turn ALS-like neuronal damage. Results show that RIPK1 inflicts damage by directly attacking the body’s myelin production plants, nerve cells known as oligodendrocytes, which secrete the soft substance, rich in fat and protein that wraps around axons to support their function and shield them from damage.
The team also examined neurons obtained from mice with the most common inherited form of ALS, one caused by mutations in a gene called SOD1. They observed that RIPK1 levels were elevated in those cells too. The group hypothesize that optineurin may not be the sole gene regulating RIPK1’s behaviour; instead, RIPK1 appears to fuel axonal damage across various forms of inherited and acquired forms of ALS.
Building on previous work from the lab showing that the activity of RIPK1 could be blocked by a chemical called necrostatin-1, the group used necrostatin-1 to treat mice with axonal damage and hind leg weakness, a telltale sign of axonal demise similar to the muscle weakness that occurs in the early stages of ALS in humans. Results show that Necrostatin-1 not only restored the myelin sheath and stopped axonal damage, it also prevented limb weakness in animals treated with it.
The team surmise that their findings suggest RIPK1 may be involved in a range of other neurodegenerative diseases marked by axonal damage, including multiple sclerosis, certain forms of spinal muscular atrophy and even Alzheimer’s disease. For the future, the researchers state that the Harvard Office of Technology Development (OTD) and collaborating institutions have developed a patent portfolio for RIPK1 modulating compounds.
Source: Harvard Medical School
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