In a breakthrough finding, researchers have discovered to successfully switch off a key route for nerve fibre failure in debilitating neurodegenerative diseases such as Parkinson’s, glaucoma, and traumatic brain injury.
The study led by Institute for Glycomics and Disarm therapeutics at Griffith University explains the structural processes behind activation and inhibition of SARM1 – a major molecule for the damage of nerve fibers.
The understanding of action of SARM1 is important to help to treat several neurodegenerative conditions, which is a trigger for nerve fiber degeneration.
Importantly, the study demonstrates the molecular interactions that can switch SARM1 on and off. This provides a clear path for the design of new drug therapeutics.
Meanwhile, for neurodegenerative disorders such as Parkinson’s, peripheral neuropathy, traumatic brain injury, and glaucoma, the damage of nerve fibers activates SARM1.
This triggers a series of molecular processes that lead to self-destruction of axon of the nerve cell – the cable that transmits electric impulse away from one nerve cell to the other.
Anatomically, the axon is several times thinner than a human hair, but is up to a meter in length. It stretches from brain to the spinal cord, and its destruction can lead to serious dysfunction.
The SARM1 protein works like a sensor and responds to the environment. The molecule switches on when the levels of nicotinamide mononucleotide, which is a small activator molecule increases. The activator molecule attaches to the larger SARM1 protein like a key in a lock thereby initiating the process that lead to the breakdown of nerve fibers. SARM1 when unlocked is able to disintegrate another key molecule called nicotinamide adenine dinucleotide, which provides energy for nerve fibers to function and continue to live.
According to clinical data, traumatic brain injury is a major cause of cognitive impairment that affects a very large population worldwide. Despite rising awareness of the debilitating and lifelong advancing consequences of traumatic brain injury (TBI), currently there are no treatments that slow the degenerative process. In fact, TBI survivors are currently treated with extensive cognitive and physical rehabilitation, along with medications that can alleviate symptoms, yet do not stop or slow degeneration.
For the first time, researchers have found that the process of this chronic health condition can be pharmacologically reversed in animal models. This offers an important proof of principle in the field and a potential path to new therapy. The findings of the study carried out by researchers at the School of Medicine, Case Western Reserve University and Harrington Discovery Institute, University Hospitals recently published in the Proceedings of the National Academy of Sciences.
TBI associated with age-related dementia, according to clinical knowledge
“In fact, TBI can have lifelong detrimental effects on a number of aspects of health,” explains the senior author of the study. Meanwhile, cognitive dysfunction, sensorimotor impairment, or emotional dysregulation such as anxiety and depression are commonly associated long-term outcomes of TBI. In addition, the risk of developing age-related forms of dementia such as Parkinson’s diseases and Alzheimer’s significantly increased with TBI.
Hence, the team set out to establish if reversing lifelong chronic neurodegeneration and associated cognitive defects after TBI is possible, which was earlier never demonstrated. For this, the team use a mouse model that imitated concussive impact in middle-aged people who suffered from TBI a decades prior. Also, an energy-elevating neuroprotective compound administered known as P7C3-A20, which was previously shown to have therapeutic value for acute TBI.