CEREBELLAR PATHOLOGY CONTRIBUTES TO MOTOR AND COGNITIVE DEFICITS IN SPINAL MUSCULAR ATROPHY

Spinal muscular atrophy (SMA) is a motor neuron disease caused by SMN deficiency, resulting in muscle weakness and impaired movement due to the degeneration of spinal motor circuits. Recent clinical findings suggest that neuronal circuits in the brain contribute to motor and deficits in SMA patients. Here, we discover conserved mechanisms of cerebellar circuit pathology associated with progressive Purkinje cell (PC) degeneration selectively in a severe mouse model and Type I SMA patients. Cerebellar pathology is further aggravated by synaptic loss and dysfunction of parallel fibers onto PCs, resulting into reduced functional output of the cerebellar cortex. These impairments arise intrinsically within the cerebellum, independent of established spinal motor circuit pathologies, and contribute to motor deficits in SMA mice. This was further proven via Cre-dependent knockdowns of Smn in PCs, where animals exhibited at old ages, severe and progressive PC degeneration. This resulted in severe motoric impairment in these animals. The PC loss found in the SMA mice on the other hand resulted in early development cognitive impairment, which presented itself with severe reduction in ultrasonic vocalizations, which was partially rescued by PC-selective restoration of SMN. Importantly, treatment with different, clinically-relevant SMN inducing therapies including splicing modifiers and gene replacement demonstrate both overlapping and distinct effects on cerebellar pathology in SMA mice. Together, these findings highlight dysfunction of cerebellar circuits and death of PCs as critical yet underappreciated contributors to motor deficits, which should be considered in care of SMA patients receiving current treatments and for development of future therapeutics.