Spinal bulbar muscular atrophy (SBMA) is a rare genetic disease that causes progressive muscle weakness and wasting in men. Patients usually develop early symptoms, such as hand tremors, in their 30s, but muscle weakness is usually diagnosed around age 40. This disease is caused by high levels of testosterone, so only men are affected.
Researchers at Nagoya University found that in newborn mice with the SBMA mutation, the natural release of testosterone immediately after birth causes the mutant protein to overactivate nerve cells (motor neurons) that control muscles. This continued overactivation ultimately leads to the destruction of these neurons in adulthood. The survey results are nature communicationsshowed that treatment given at birth significantly reduces this breakdown.
It is well established that the accumulation of abnormal proteins in neurodegenerative diseases begins years or decades before symptoms appear, but what actually happens in the body during this period is still poorly understood. This study focused on the early stages of SBMA, the first few days of life.
A brief, natural spike in testosterone, known as the neonatal testosterone surge or “mini-puberty,” occurs in all newborn males and lasts about 10 days in mice and about 6 months in humans. Because the defective protein produced by the SBMA mutation (mutant androgen receptor protein) requires testosterone to travel to the nucleus of motor neurons and cause damage, the researchers suspected that this surge might represent the earliest moment when the disease is triggered.
We found that a neonatal surge of testosterone caused the mutant protein to accumulate in the motor neuron nuclei of male SBMA mice within the first day of life. No such effect was seen in female mice carrying the same mutation, confirming that testosterone was an important trigger. ”
Tomokki Hirunagi (first author, Assistant Professor, Nagoya University Graduate School of Medicine)
Furthermore, genes involved in the activation of nerve cells, particularly glutamate receptors, became abnormally overactive in the SBMA mice during the first week of life, leading to hyperactivity of motor neurons. Importantly, the same abnormal hyperactivity was also observed in motor neurons grown in the lab from cells from actual SBMA patients. This suggests that human disease processes may follow the same pattern.
To test whether treating the disease at birth would be effective, the researchers administered two gene-suppressing drugs to newborn mice carrying the SBMA mutation. One drug targets the mutant protein directly, and the other targets REST4, a protein found to cause abnormal nerve cell overactivity.
Drugs targeting the mutant protein temporarily reduced mutant protein levels, and drugs targeting REST4 corrected aberrant gene activity in motor neurons. Both treatments improved survival and motor performance and reduced motor neuron degeneration in mice assessed at 13 weeks of age.
“Perhaps the most remarkable finding was that a drug given at birth to target the mutant protein continued to protect motor neurons months later, even though the drug’s effects wore off within two weeks. This suggests that timely intervention early in life may have lasting results even after treatment has ended,” Dr. Hirunagi said.
REST4 is a protein found to cause abnormal neuronal hyperactivity in SBMA and may represent a new target for future treatments.
Nagoya University previously developed leuprorelin acetate, the only drug approved in Japan to treat SBMA, and these discoveries form part of a broader research legacy in tackling the disease.
The research team identified that their next priority was to determine whether the same abnormal nerve cell hyperactivity also occurs in human SBMA patients. “It is currently very difficult to study this directly, as it is not practical to examine the activity of the neonatal nervous system in living patients. Our goal is to translate these findings into patient care,” Dr. Hirnagi said. The research team also plans to evaluate the safety of the gene-suppressing drug and the effectiveness of repeated treatments.
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Reference magazines:
Hirunagi, T. Others. (2026). Reversing early postnatal synaptic dysregulation reverses motor neuron degeneration in a mouse model of spinal and spinal muscular atrophy. Nature Communications. DOI: 10.1038/s41467-026-70244-2. https://www.nature.com/articles/s41467-026-70244-2.
