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ABSTRACT

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by ubiquitous SMN deficiency and loss of motor neurons. The persistence of motor and communication impairments, together with emerging cognitive and social deficits in severe Type I SMA patients treated early with SMN-restoring therapies, suggests a broader dysfunction involving neural circuits of the brain. To explore the potential supraspinal contributions to these emerging phenotypes, we investigated the cerebellum, a brain region critical for both motor and cognitive behaviors. Here, we identify cerebellar pathology in both post-mortem tissue from Type I SMA patients and a severe mouse model, which is characterized by lobule-specific Purkinje cell (PC) death driven by cell-autonomous, non-apoptotic p53-dependent mechanisms. Loss and dysfunction of excitatory parallel fiber synapses onto PC further contribute to cerebellar circuit disruption and altered PC firing. Furthermore, we identified impaired ultrasonic vocalization (USV) in a severe SMA mouse model—a proxy for early-developing social communication skills that depend on cerebellar function. Cell-specific rescue experiments demonstrate that intrinsic cerebellar pathology contributes to motor and social communication impairments independently of spinal motor circuit abnormalities. Together, these findings establish cerebellar dysfunction as a pathogenic driver of motor and social deficits, providing a link between brain involvement and the emerging neurodevelopmental phenotypes of SMA.

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