The p17 transporter in mice leads to the accumulation of damaged and disorganized membranes in axonal mitochondria. This accumulation ultimately results in the degeneration of myelinated neuronal axons (shown in green) following mild, repetitive traumatic brain injury. Credit: Karakaya et al.
Repeated concussions, also called repetitive mild traumatic brain injury, can lead to chronic traumatic encephalopathy (CTE) and increase the risk of Alzheimer’s disease. However, some people who experience mild, repeated head trauma never develop serious illness.
Onder Albayram and colleagues studied the role of a protein known as p17 in protecting the brain against long-term pathologies. In stressed neurons, p17 initiates the production of C18-Ceramide, a bioactive sphingolipid that acts as a marker of damaged mitochondria in neuronal axons. The study is published in the journal Nexus PNAS.
The labeled mitochondria are then detected and eliminated by autophagosomes. The authors knocked out p17 in mice. Some p17 knockout mice underwent a novel experimental model of repetitive concussion brain injury, known as the less-than-mild repetitive closed head injury (rlmTBI) paradigm.
These mice developed significant sensorimotor deficits after three months. After six months, the mice showed cognitive deficits. Control mice did not show any behavioral disorders.
In the brains of rlmTBI p17 knockout mice, the authors found compromised and disordered membranes in axonal mitochondria. In normal mice, these mitochondria would have been destroyed, but since this process was disrupted, the dysfunctional organelles persisted and caused axonal degeneration, which in turn led to pathological consequences.
The authors developed a mitochondria-targeted pyridinium-ceramide analogue drug, LCL768, which accumulates in damaged mitochondria and restores the process by which these organelles are cleared.
In mice, treatment with LCL768 prevented the development of secondary axonal degeneration and resulted in improved functional outcomes compared to mice given placebo.
Finally, the authors examined human tissues from six neuropathologically verified cases of CTE with a history of repetitive head trauma. CTE-positive samples showed less expression of p17 and less mitochondrial C18-Ceramide than six age- and sex-matched healthy control samples.
According to the authors, drugs that ensure a healthy pool of axonal mitochondria in the brain could be candidates for use as prophylactic treatment after a concussion.
More information:
Eda Karakaya et al, p17/C18 ceramide-mediated mitophagy is an endogenous neuroprotective response in preclinical and clinical brain injury, Nexus PNAS (2024). DOI: 10.1093/pnasnexus/pgae018
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Quote: New drug could protect the brain from damage caused by repeated concussions (February 7, 2024) retrieved February 7, 2024 from
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