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@ARTICLE{Gerstner:285477,
      author       = {Gerstner, Florian and Wittig, Sandra and Menedo, Christian
                      and Ruwald, Sayan and Carlini, Maria J and Vankova, Adela
                      and Sowoidnich, Leonie and Martín-López, Gerardo and
                      Dreilich, Vanessa and Alonso-Collado, Andrea and Pagiazitis,
                      John G and Aousji, Oumayma and Grzyb, Chloe and Smith, Amy K
                      and Yang, Mu and Roselli, Francesco and Mentis, George Z and
                      Sumner, Charlotte J and Pellizzoni, Livio and Simon,
                      Christian M},
      title        = {{C}erebellar pathology contributes to neurodevelopmental
                      deficits in spinal muscular atrophy.},
      journal      = {Brain},
      volume       = {149},
      number       = {3},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2026-00254},
      pages        = {840 - 855},
      year         = {2026},
      abstract     = {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.},
      keywords     = {Animals / Mice / Cerebellum: pathology / Cerebellum:
                      physiopathology / Humans / Purkinje Cells: pathology / Male
                      / Disease Models, Animal / Female / Muscular Atrophy,
                      Spinal: pathology / Neurodevelopmental Disorders: pathology
                      / Neurodevelopmental Disorders: etiology / Motor Neurons:
                      pathology / Mice, Inbred C57BL / autism-like behaviour
                      (Other) / cerebellar circuit dysfunction (Other) / motor
                      neuron diseases (Other) / neuronal death (Other) / social
                      deficits (Other)},
      cin          = {AG Roselli},
      ddc          = {610},
      cid          = {I:(DE-2719)1910001},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40966716},
      pmc          = {pmc:PMC12908613},
      doi          = {10.1093/brain/awaf336},
      url          = {https://pub.dzne.de/record/285477},
}