Repeated brain injury quickens ALS onset and progression in mice
Animals without Sarm1 gene saw reduced effects from TBI
Repeated traumatic brain injuries (TBIs), which happen when the brain is damaged by external impacts such as a fall or a car accident, can accelerate the onset and progression of amyotrophic lateral sclerosis (ALS) associated with mutations in the SOD1 gene, a new mouse study suggests.
The effects of TBI in ALS mice, including nerve cell loss, neuroinflammation, and reduced survival, were all reduced in animals who lacked the Sarm1 gene, which has been implicated in the degeneration of nerve fibers in humans.
For this reason, “therapeutics targeting the Sarm1 pathway are a viable approach to preserve neurological function in injury-accelerated [familial] ALS,” the researchers wrote. The study “Genetic Ablation of Sarm1 Mitigates Disease Acceleration after Traumatic Brain Injury in the SOD1G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis,” was published in the Annals of Neurology.
Traumatic brain injuries have been shown to increase the risk of ALS and other neurodegenerative conditions. Such injuries are common in people who play contact sports, for example, and can lead to features related to ALS, including the loss of nerve cells, along with the formation of toxic TDP-43 clumps that damage neurons.
Effect of TBI on SOD1 mutations
Here, scientists at the University of Massachusetts Chan Medical School investigated the impact of repetitive TRI in a mouse model of SOD1-ALS to see if it accelerates the onset and progression of ALS in people carrying SOD1 mutations, which are seen in about 20% of familial ALS and 2% of sporadic cases.
The researchers also bred ALS mice lacking Sarm1, a gene coding for a protein that’s a central regulator of nerve fiber degeneration in humans. Blocking the activity of Sarm1 has been shown to prevent nerve fiber degeneration in ALS mice. Also, SARM1 mutations have been linked to ALS and ASHA-624, an experimental SARM1-blocking therapy, is about to enter clinical testing.
All the mice underwent induced TBI, or sham injury as a control, once daily for five consecutive days at 9 weeks of age, when they still had no symptoms of ALS.
Repetitive TBI did accelerate the onset and progression of ALS in the SOD1-ALS mice, as indicated by greater weight loss, an earlier onset of tremor in the hind limbs, and shortened survival. TBI also triggered two neuroinflammatory responses to brain injury: microgliosis, which refers to the excess activation of microglia, the brain’s immune cells, and astrocytosis, or an overactivation of the supporting, star-shaped cells called astrocytes. Both microgliosis and astrocytosis are believed to be implicated in ALS.
“This suggests that TBI could initiate disease onset in carriers of the SOD1-ALS gene mutation by promoting neurotoxic transformation of astroglia,” the researchers wrote.
Moreover, TBI promoted the mislocalization of TDP-43, which is normally found in the nucleus, but forms clumps in the cytoplasm in ALS nerve cells. This “raises the intriguing possibility that the presence of TDP-43 [disease] in some human cases could be linked to preceding brain injury,” the researchers wrote.
In sham-injured control ALS mice, deleting the Sarm1 gene had no impact on survival, neurological deficits, nerve fiber loss, or TDP-43 mislocalization. In turn, most of the neurological deficits induced by TBI were attenuated in animals lacking the Sarm1 gene.
“Our data show that rTBI [repeated TBI] accelerates disease onset and worsens survival” in SOD1-ALS mice, the researchers wrote. “Genetic ablation of Sarm1 diminishes the impact of rTBI on disease onset and survival, and rescues features of rTBI-associated pathology including TDP-43 mislocalization, neuronal and axonal loss, and neuroinflammation.”
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