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000285477 041__ $$aEnglish
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000285477 1001_ $$aGerstner, Florian$$b0
000285477 245__ $$aCerebellar pathology contributes to neurodevelopmental deficits in spinal muscular atrophy.
000285477 260__ $$aOxford$$bOxford Univ. Press$$c2026
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000285477 520__ $$aSpinal 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.
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000285477 650_7 $$2Other$$aautism-like behaviour
000285477 650_7 $$2Other$$acerebellar circuit dysfunction
000285477 650_7 $$2Other$$amotor neuron diseases
000285477 650_7 $$2Other$$aneuronal death
000285477 650_7 $$2Other$$asocial deficits
000285477 650_2 $$2MeSH$$aAnimals
000285477 650_2 $$2MeSH$$aMice
000285477 650_2 $$2MeSH$$aCerebellum: pathology
000285477 650_2 $$2MeSH$$aCerebellum: physiopathology
000285477 650_2 $$2MeSH$$aHumans
000285477 650_2 $$2MeSH$$aPurkinje Cells: pathology
000285477 650_2 $$2MeSH$$aMale
000285477 650_2 $$2MeSH$$aDisease Models, Animal
000285477 650_2 $$2MeSH$$aFemale
000285477 650_2 $$2MeSH$$aMuscular Atrophy, Spinal: pathology
000285477 650_2 $$2MeSH$$aNeurodevelopmental Disorders: pathology
000285477 650_2 $$2MeSH$$aNeurodevelopmental Disorders: etiology
000285477 650_2 $$2MeSH$$aMotor Neurons: pathology
000285477 650_2 $$2MeSH$$aMice, Inbred C57BL
000285477 7001_ $$aWittig, Sandra$$b1
000285477 7001_ $$aMenedo, Christian$$b2
000285477 7001_ $$aRuwald, Sayan$$b3
000285477 7001_ $$aCarlini, Maria J$$b4
000285477 7001_ $$aVankova, Adela$$b5
000285477 7001_ $$aSowoidnich, Leonie$$b6
000285477 7001_ $$aMartín-López, Gerardo$$b7
000285477 7001_ $$aDreilich, Vanessa$$b8
000285477 7001_ $$aAlonso-Collado, Andrea$$b9
000285477 7001_ $$aPagiazitis, John G$$b10
000285477 7001_ $$aAousji, Oumayma$$b11
000285477 7001_ $$aGrzyb, Chloe$$b12
000285477 7001_ $$aSmith, Amy K$$b13
000285477 7001_ $$aYang, Mu$$b14
000285477 7001_ $$0P:(DE-2719)2812851$$aRoselli, Francesco$$b15
000285477 7001_ $$aMentis, George Z$$b16
000285477 7001_ $$aSumner, Charlotte J$$b17
000285477 7001_ $$aPellizzoni, Livio$$b18
000285477 7001_ $$aSimon, Christian M$$b19
000285477 773__ $$0PERI:(DE-600)1474117-9$$a10.1093/brain/awaf336$$gVol. 149, no. 3, p. 840 - 855$$n3$$p840 - 855$$tBrain$$v149$$x0006-8950$$y2026
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