TY  - JOUR
AU  - Gerstner, Florian
AU  - Wittig, Sandra
AU  - Menedo, Christian
AU  - Ruwald, Sayan
AU  - Carlini, Maria J
AU  - Vankova, Adela
AU  - Sowoidnich, Leonie
AU  - Martín-López, Gerardo
AU  - Dreilich, Vanessa
AU  - Alonso-Collado, Andrea
AU  - Pagiazitis, John G
AU  - Aousji, Oumayma
AU  - Grzyb, Chloe
AU  - Smith, Amy K
AU  - Yang, Mu
AU  - Roselli, Francesco
AU  - Mentis, George Z
AU  - Sumner, Charlotte J
AU  - Pellizzoni, Livio
AU  - Simon, Christian M
TI  - Cerebellar pathology contributes to neurodevelopmental deficits in spinal muscular atrophy.
JO  - Brain
VL  - 149
IS  - 3
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2026-00254
SP  - 840 - 855
PY  - 2026
AB  - Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by ubiquitous survival motor neuron (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 crucial for both motor and cognitive behaviours. 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 death driven by cell-autonomous, non-apoptotic p53-dependent mechanisms. Loss and dysfunction of excitatory parallel fibre synapses onto Purkinje cells contribute further to cerebellar circuit disruption and altered Purkinje cell firing. Furthermore, we identified impaired ultrasonic vocalization (a proxy for early-developing social communication skills that depend on cerebellar function) in a severe SMA mouse model. 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 neurodevelopmental motor and social defects, providing mechanistic insight into the persisting and emerging phenotypes of SMA.
KW  - Animals
KW  - Mice
KW  - Cerebellum: pathology
KW  - Cerebellum: physiopathology
KW  - Humans
KW  - Purkinje Cells: pathology
KW  - Male
KW  - Disease Models, Animal
KW  - Female
KW  - Muscular Atrophy, Spinal: pathology
KW  - Neurodevelopmental Disorders: pathology
KW  - Neurodevelopmental Disorders: etiology
KW  - Motor Neurons: pathology
KW  - Mice, Inbred C57BL
KW  - autism-like behaviour (Other)
KW  - cerebellar circuit dysfunction (Other)
KW  - motor neuron diseases (Other)
KW  - neuronal death (Other)
KW  - social deficits (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40966716
C2  - pmc:PMC12908613
DO  - DOI:10.1093/brain/awaf336
UR  - https://pub.dzne.de/record/285477
ER  -