Cerebellar pathology contributes to neurodevelopmental deficits in spinal muscular atrophy

TL;DR

The study shows that cerebellar dysfunction contributes to motor and communication issues in spinal muscular atrophy, beyond motor neuron loss.

Contribution

The study reveals cerebellar pathology in SMA, including Purkinje cell death and impaired communication, independent of spinal motor issues.

Findings

Cerebellar pathology, including Purkinje cell death, is observed in SMA patients and mouse models.

Impaired ultrasonic vocalization in SMA mice suggests cerebellar involvement in social communication.

Cerebellar dysfunction contributes to motor and communication deficits independently of spinal issues.

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 identify a pathogenic role for cerebellar dysfunction and broaden the understanding of SMA as a multi-regional neurodevelopmental disorder.

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