Mice expressing the α_1B‐adrenergic receptor induces a synucleinopathy with excessive tyrosine nitration but decreased phosphorylation

Abstract

We had previously reported that systemic overexpression of the a 1B -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 a-synuclein and ubiquitin, and therefore may be classified as a synucleinopathy. a-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 a-synuclein, which also increased its nitrated content with age.However, the same extracts displayed decreased phosphorylation of a-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 a 1 -AR antagonist, terazosin, resulted in protection against the symptomatic as well as the neurodegeneration and a-synuclein inclusion body formation, suggesting that signaling of the a 1B -AR is the cause of the pathology. We conclude that overexpression of the a 1B -AR can cause a synucleinopathy similar to other parkinsonian syndromes.

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

“…However, no previous studies followed all animals until the natural date of death. In the current study, the survival of CAM-α 1B AR animals began to deviate from that of WT mice at approximately 9 months of age, the timing of which coincides with the pathological appearance of neurodegeneration and the age at which body weight begins to differ (Papay et al 2002). The α 1 AR antagonist terazosin protects these mice against the weight loss and neurodegeneration.…”

“…Our WT B6CBA animals had a median age of 719 days, which is between the two strains, but slightly closer to the CBA/J median age. Prior to this work, survival had been assessed in CAM-α 1B AR mice, then called T1 mice, for up to 70 weeks (Papay et al 2002). However, no previous studies followed all animals until the natural date of death.…”

“…In transgenic models of increased α 1B AR activity, a maladaptive cardiac hypertrophy was either present at baseline or developed over time concomitantly with other cardiac and cardiacrelated deficits (reviewed in Perez and Doze 2011). Chronic α 1B AR activity also leads to age-related apoptotic neurodegeneration, a synucleinopathy with Parkinson-like movement deficits similar to human multiple system atrophy (Zuscik et al 2000;Papay et al 2002). The neurodegeneration begins in areas of the brain with a high density of α 1B ARs and leads to a substantial loss of dopaminergic neurons in the substantia nigra.…”

Neurological and Neurodegenerative Alterations in a Transgenic Mouse Model Expressing Human α-Synuclein under Oligodendrocyte Promoter: Implications for Multiple System Atrophy

“…Furthermore, radical oxygen species promote h␣-syn aggregation Ischiropoulos and Beckman, 2003), and oxidized forms of this molecule have been identified in oligodendrocytes in the brains of patients with MSA (Gomez-Tortosa et al, 2002). Consistent with this possibility, a recent study using tg mice systemically overexpressing the ␣ 1B -adrenergic receptor that resembled the parkinsonian-like features of MSA showed increased expression of ␣-syn and markers of oxidative stress (Papay et al, 2002). Additionally, glial cells overexpressing h␣-syn display increased vulnerability to oxidative stress, particularly in the presence of cytoplasmic inclusions (Stefanova et al, 2001).…”

α1-Adrenergic Receptors Regulate Neurogenesis and Gliogenesis

“…␣ 1A -AR activation cojoined with specific ␣ 1B -AR antagonism may be a preferred treatment option because ␣ 1B -AR blockage protects against ␣-synuclein aggregates and neurotoxicity (Papay et al, 2002). In addition to regulating neurogenesis, the ␣ 1A -AR is neuroprotective against seizures and protects interneurons against age-related death (Knudson et al, 2007).…”