Mice expressing the α1B-adrenergic receptor induces a synucleinopathy with excessive tyrosine nitration but decreased phosphorylation

Abstract

We had previously reported that systemic overexpression of the α1B-adrenergic receptor (AR) in a transgenic mouse induced a neurodegenerative disease that resembled the parkinsonian-like syndrome called multiple system atrophy (MSA). We now report that our mouse model has cytoplasmic inclusion bodies that colocalize with oligodendrocytes and neurons, are positive for α-synuclein and ubiquitin, and therefore may be classified as a synucleinopathy. α-Synuclein monomers as well as multimers were present in brain extracts from both normal and transgenic mice. However, similar to human MSA and other synucleinopathies, transgenic mice showed an increase in abnormal aggregated forms of α-synuclein, which also increased its nitrated content with age. However, the same extracts displayed decreased phosphorylation of α-synuclein. Other traits particular to MSA such as Purkinje cell loss in the cerebellum and degeneration of the intermediolateral cell columns of the spinal cord also exist in our mouse model but differences still exist between them. Interestingly, long-term therapy with the α1-AR antagonist, terazosin, resulted in protection against the symptomatic as well as the neurodegeneration and α-synuclein inclusion body formation, suggesting that signaling of the α1B-AR is the cause of the pathology. We conclude that overexpression of the α1B-AR can cause a synucleinopathy similar to other parkinsonian syndromes.