Zuscik MJ, Sands S, Ross SA, Waugh DJJ, Gaivin RJ, Morilak D et al. Overexpression of the 1B-adrenergic receptor causes apoptotic neurodegeneration: multiple system atrophy. Nat Med 6: 1388-1394

Department of Molecular Cardiology NB50, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
Nature Medicine (Impact Factor: 27.36). 01/2001; 6(12):1388-94. DOI: 10.1038/82207
Source: PubMed


Progress toward elucidating the function of alpha1B-adrenergic receptors (alpha1BARs) in the central nervous system has been constrained by a lack of agonists and antagonists with adequate alpha1B-specificity. We have obviated this constraint by generating transgenic mice engineered to overexpress either wild-type or constitutively active alpha1BARs in tissues that normally express the receptor, including the brain. All transgenic lines showed granulovacular neurodegeneration, beginning in alpha1B-expressing domains of the brain and progressing with age to encompass all areas. The degeneration was apoptotic and did not occur in non-transgenic mice. Correspondingly, transgenic mice showed an age-progressive hindlimb disorder that was parkinsonian-like, as demonstrated by rescue of the dysfunction by 3, 4-dihydroxyphenylalanine and considerable dopaminergic-neuronal degeneration in the substantia nigra. Transgenic mice also had a grand mal seizure disorder accompanied by a corresponding dysplasia and neurodegeneration of the cerebral cortex. Both behavioral phenotypes (locomotor impairment and seizure) could be partially rescued with the alpha1AR antagonist terazosin, indicating that alpha1AR signaling participated directly in the pathology. Our results indicate that overstimulation of alpha1BAR leads to apoptotic neurodegeneration with a corresponding multiple system atrophy indicative of Shy-Drager syndrome, a disease whose etiology is unknown.

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    • "Along with this, METH-induced behavioural effects and DA neurotoxicity are prevented [130]. This is further confirmed by the finding that mice overexpressing alpha1b adrenoceptors are characterized by spontaneous nigrostriatal DA toxicity [131]. Alpha1, alpha1 adrenoceptor; Alpha1b, alpha1b adrenoceptors; D2, D2 dopamine receptor; mAChR, muscarinic receptor; METH, methamphetamine; mGluR, metabotropic glutamate receptor; PI, phosphoinositide pathway. "
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    ABSTRACT: The activity of locus coeruleus (LC) neurons has been extensively investigated in a variety of behavioural states. In fact this norepinephrine (NE)-containing nucleus modulates many physiological and pathological conditions including the sleep-waking cycle, movement disorders, mood alterations, convulsive seizures, and the effects of drugs such as psychostimulants and opioids. This review focuses on the modulation exerted by central NE pathways on the behavioural and neurotoxic effects produced by the psychostimulant methamphetamine, essentially the modulation of the activity of mesencephalic dopamine (DA) neurons. In fact, although NE in itself mediates some behavioural effects induced by methamphetamine, NE modulation of DA release is pivotal for methamphetamine-induced behavioural states and neurotoxicity. These interactions are discussed on the basis of the state of the art of the functional neuroanatomy of central NE- and DA systems. Emphasis is given to those brain sites possessing a remarkable overlapping of both neurotransmitters.
    Current Neuropharmacology 01/2013; 11(1):80-94. DOI:10.2174/157015913804999522 · 3.05 Impact Factor
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    • "Transgenic overexpression of α1B-adrenergic receptors (α1B-AR) in mice generated wide-spread neurodegeneration linked to seizures (Zuscik et al., 2000; Kunieda et al., 2002), as well as cardiovascular autonomic dysfunction and motor impairment resembling MSA. This phenotype was associated with the formation of neuronal and oligodendroglial αSYN inclusions by yet unclear mechanisms (Papay et al., 2002; Zuscik et al., 2000, 2001). More recent evidence of increased MSA risk conferred by polymorphisms within the αSYN gene (Scholz et al., 2009; Al-Chalabi et al., 2009) corroborates the validity of the transgenic αSYN MSA models (Stefanova et al., 2005b). "
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    ABSTRACT: Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause manifesting with progressive autonomic failure (AF), cerebellar ataxia and parkinsonism due to neuronal loss in multiple brain areas associated with (oligodendro)glial cytoplasmic alpha-synuclein (alpha SYN) inclusions (GCIs). Using proteolipid protein (PLP)-alpha-synuclein (alpha SYN) transgenic mice we have previously reported parkinsonian motor deficits triggered by MSA-like alpha SYN inclusions. We now extend these observations by demonstrating degeneration of brain areas that are closely linked to progressive AF and other non-motor symptoms in MSA, in (PLP)-alpha SYN transgenic mice as compared to age-matched non-transgenic controls. We show delayed loss of cholinergic neurons in nucleus ambiguus at 12 months of age as well as early neuronal loss in laterodorsal tegmental nucleus, pedunculopontine tegmental nucleus and Onuf's nucleus at 2 months of age associated with alpha SYN oligodendroglial overexpression. We also report that neuronal loss triggered by MSA-like alpha SYN inclusions is absent up to 12 months of age in the thoracic intermediolateral cell column suggesting a differential dynamic modulation of alpha SYN toxicity within the murine autonomic nervous system. Although the spatial and temporal evolution of central autonomic pathology in MSA is unknown our findings corroborate the utility of the (PLP)-alpha SYN transgenic mouse model as a testbed for the study of oligodendroglial alpha SYN mediated neurodegeneration replicating both motor and non-motor aspects of MSA.
    Experimental Neurology 08/2010; 224(2):459-64. DOI:10.1016/j.expneurol.2010.05.008 · 4.70 Impact Factor
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    • "The fortuitous discovery that transgenic mice over-expressing the 1B-adrenergic receptor bear several features with MSA, speared curiosity among researchers, as implication of the NE transmission in the pathogenesis of MSA was never previously suspected (Zuscik et al. 2000). Although the group that has developed these mice do acknowledge that MSA is not due to a mutated form of this receptor, this transgenic model may nevertheless be useful in dissecting the neurotransmission pathway that might be implicated in this disease. "
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    ABSTRACT: The use of animals as models of neurodegenerative disorders has allowed the determination of biological targets and biomarkers of several diseases, has yielded new therapeutical perspectives, and is essential before performing novel clinical assays. This review discusses the nature, use, and limits of animal models and how to obtain them for several neurodegenerative disorders such as multiple system atrophy, amyotrophic lateral sclerosis, and Huntington’s disease, with a special emphasis on Parkinson’s and Alzheimer’s diseases. When possible, rodent, invertebrate and primate models are presented and discussed in relation to human disease. Finally, we highlight discrepancies between animal models and human neuropathology leading to question the pertinence of some of these findings to human disorders probably because of the wide spectrum of parameters defining a disease. Another point raised by these studies is the growing necessity to standardize the experimental procedures used to obtain an animal model, housing and breeding conditions, assessments of phenotypes investigated and, ultimately the interpretation of results obtained and their relevance to the pathology. KeywordsParkinson’s disease-Huntington disease-Alzheimer’s disease-Amyotrophic lateral sclerosis-Multiple system atrophy-Tauopathies-Nucleotide repeats
    01/2010: pages 49-101;
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