Spinal muscular atrophy is a rare genetic disease of the nerve cells in the spinal cord that can appear as early as infancy. The disease leads to a progressive loss of muscle strength. Those affected often suffer from muscle weakness early on, as well as difficulties with movement, breathing, and swallowing. Thanks to medical advances, therapies are now available that slow the progression of the disease. Nevertheless, motor impairments persist, and cognitive and social challenges become increasingly evident.
For a long time, spinal muscular atrophy was understood solely as a disease of the motor neurons, in which those nerve cells that directly control the muscles lose their function. In recent years, however, researchers have been able to show that other nerve cells in the spinal cord, which do not directly control the muscles, also contribute to the disease. Building on these findings, researchers at Leipzig University's Carl Ludwig Institute of Physiology have now investigated whether additional regions of the nervous system are involved in the development of spinal muscular atrophy.
In the new study, they discovered that the cerebellum also contributes to the development of the disease. "Our results make it clear that the cerebellum is not only affected by the disease but is itself an independent driver of the symptoms. These latest findings therefore provide a possible explanation for the persistent motor impairments and the newly emerging social and cognitive problems experienced by patients despite modern therapies," says Dr Christian Simon, head of the study and researcher at the Faculty of Medicine.
In their investigations, the Leipzig researchers were able to show that Purkinje cells – key nerve cells of the cerebellum – are damaged in spinal muscular atrophy. The cause is the activation of a specific signalling pathway that leads to cell death and severe disruptions in cerebellar networks. The consequences became apparent in the mouse model: animals with spinal muscular atrophy not only exhibited motor impairments but also showed markedly reduced communicative activity, expressed in diminished ultrasonic vocalisations – high-frequency sounds that mice normally use to communicate. By specifically restoring the missing protein in the Purkinje cells, it was possible to partially improve both the motor and the social deficits.
The Carl Ludwig Institute of Physiology has extensive expertise in cerebellar physiology. For these investigations, high-resolution imaging and patch-clamp recordings were carried out on cerebellar slices from mice. In addition, the Leipzig researchers used viral vectors to specifically manipulate gene expression in the mice.
A special feature of this scientific work is that three of the four first authors are medical students who contributed to this publication as part of their doctoral research. They were partly supported by doctoral scholarships from the Faculty of Medicine. International collaborations with Columbia University, Johns Hopkins University, and Ulm University provided crucial support for the project.
"Our research provides an important basis for further studies that aim to investigate changes in the cerebellum in spinal muscular atrophy in larger groups of patients. As a next step, we want to test existing therapies in our mouse models to see whether the cerebellar changes and the associated social symptoms of the disease can be improved," says Dr Simon.
