Mechanisms of cerebellar pathology in spinal muscular atrophy

• Applicant: Dr. Christian Simon
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558123990

Spinal muscular atrophy (SMA) is characterized by the degeneration of spinal motor neurons resulting in impaired voluntary movement and muscle atrophy. SMA is caused by the deficiency of the SMN protein. SMN restoring approaches have been proven to successfully ameliorate the disease manifestations in SMA patients and mouse models. However, it is widely appreciated that these SMN restoring therapies are not a cure for the disease as not all SMA patients respond to the treatment. One therapeutic limitation may be that yet unidentified vulnerable cells are not being sufficiently targeted by SMN treatment. Therefore, future studies focusing on the discovery of novel neuronal groups affecting motor behavior in SMA are needed. The motor circuits in the cerebellum are critical for motor learning and voluntary movements by processing proprioceptive input and modulating motor output, which are both affected in SMA. The Purkinje cells are the sole output of the cerebellar cortex converging information from the spinal cord and different brain regions, making them key neurons for cerebellar function. In addition, Purkinje cells are reported as vulnerable neurons in several genetic diseases such as SMA and other motor neuron diseases. However, further studies are needed to conclusively characterize the mechanisms of cerebellar pathology and its contribution to the SMA phenotype. Our preliminary data identifies Purkinje cell loss accompanied by p53 pathway activation that triggers motor neuron death in SMA, cerebellar dysfunction, and gross impaired morphology across mouse models, suggesting a prominent role in SMA pathology. The goal of this proposal is to define the degree and impact of cerebellar pathology in SMA mouse models and human tissue with a central focus on the loss and dysfunction of Purkinje cells. We will combine our expertise of electrophysiology, viral gene manipulation, and imaging to successfully reach the following three specific aims in SMA pathology to determine: 1. whether p53 pathway activation triggers Purkinje cell death in SMA. 2. the neuronal and synaptic dysfunction in the cerebellar motor circuits of SMA mice. 3. the impact of cerebellar pathology on the SMA phenotype. Overall, the designed experiments of this proposal will identify the mechanisms of cerebellar pathology and its contribution to SMA motor phenotype laying ground for future therapeutic approaches.

• DFG Programme: Research Grants