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Zuscik and colleagues1 report transgenic mice with overexpression of the α1B-adrenergic receptor (α1BAR) leading to apoptotic neurodegeneration in α1B-expressing domains including cerebral cortex, hypothalamus, thalamus and cerebellum. Moreover, their model showed a reduction of tyrosine hydroxylase immunoreactivity in the substantia nigra with a loss of neuronal cell bodies and axonal projections. Transgenic mice exhibited a terazosine- and L-DOPA–responsive parkinson-like motor disorder predominantly affecting gait in association with recurrent grand mal seizures and some degree of autonomic failure. The authors propose that both the behavioural and neuropathological phenotype displayed by α1BAR transgenic mice are consistent with the autonomic (Shy–Drager) presentation of multiple system atrophy (MSA). We disagree with this conclusion. MSA is a neurodegenerative disorder that is dominated clinically by autonomic dysfunction and L-DOPA–unresponsive parkinsonism, or less commonly, cerebellar ataxia2,3. The term `Shy–Drager syndrome' has been misused in the past to encompass not only MSA, but also Parkinson disease (PD) with autonomic failure4. It was therefore abandoned by a recent consensus conference on the clinical diagnosis of MSA (ref. 5). A seizure disorder, one of the key features of the transgenic mice model described by Zuscik and colleagues, does not occur in MSA (ref. 3). Furthermore, the pattern of brain lesions present in the transgenic mouse model (beginning in cortex, hypothalamus and cerebellum, then progressing with age to encompass all brain areas) is only partially consistent with the neuropathology of MSA that is characterized by neuronal cell loss and gliosis particularly involving putamen and substantia nigra (striatonigral degeneration) as well as pons, inferior olives and cerebellar cortex (olivopontocerebellar atrophy), and preganglionic sympathetic centres in the intermediolateral cell column of the spinal cord6. In contrast, cortex and hypothalamus are relatively spared. In addition, in MSA there is prominent subcellular pathology comprising α-synuclein–positive glial and neuronal cytoplasmic and nuclear inclusions, with a distribution selectively involving basal ganglia, supplementary and primary motor cortex, reticular formation, basis pontis, middle cerebellar peduncles and cerebellar white matter6,7. Together with Parkinson Disease and dementia with Lewy bodies, MSA is increasingly conceived as α-synucleinopathy6. Although Zuscik et al. briefly mention the presence of cytoplasmic inclusions in the discussion, they do not state whether MSA-like glial and/or neuronal α-synuclein inclusions were present in the transgenic brains. We therefore conclude that Zuscik et al. provide no convincing evidence for a transgenic mouse model of MSA and instead report an unusual `seizure-plus' syndrome based on a neuronal multisystem degeneration with prominent cortical degeneration.
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Seppi, K., Puschban, Z., Stefanova, N. et al. Overstimulation of the α1B-adrenergic receptor causes a “seizure plus” syndrome. Nat Med 7, 132 (2001). https://doi.org/10.1038/84529
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DOI: https://doi.org/10.1038/84529
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