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Transgenic Mice Expressing Human α-Synuclein in Noradrenergic Neurons Develop Locus Ceruleus Pathology and Nonmotor Features of Parkinson's Disease.
Butkovich, Laura M; Houser, Madelyn C; Chalermpalanupap, Termpanit; Porter-Stransky, Kirsten A; Iannitelli, Alexa F; Boles, Jake S; Lloyd, Grace M; Coomes, Alexandra S; Eidson, Lori N; De Sousa Rodrigues, Maria Elizabeth; Oliver, Danielle L; Kelly, Sean D; Chang, Jianjun; Bengoa-Vergniory, Nora; Wade-Martins, Richard; Giasson, Benoit I; Joers, Valerie; Weinshenker, David; Tansey, Malú Gámez.
Afiliación
  • Butkovich LM; Laney Graduate School, Emory University, Atlanta, Georgia 30322.
  • Houser MC; Laney Graduate School, Emory University, Atlanta, Georgia 30322.
  • Chalermpalanupap T; Laney Graduate School, Emory University, Atlanta, Georgia 30322.
  • Porter-Stransky KA; Department of Human Genetics, Emory School of Medicine, Atlanta, Georgia 30322.
  • Iannitelli AF; Department of Human Genetics, Emory School of Medicine, Atlanta, Georgia 30322.
  • Boles JS; Department of Biomedical Sciences, Homer Stryker M.D. School of Medicine, Western Michigan University, Kalamazoo, Michigan 49008.
  • Lloyd GM; Department of Human Genetics, Emory School of Medicine, Atlanta, Georgia 30322.
  • Coomes AS; Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, Florida 32610.
  • Eidson LN; Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, Florida 32610.
  • De Sousa Rodrigues ME; Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, Florida 32610.
  • Oliver DL; Department of Physiology, Emory School of Medicine, Atlanta, Georgia 30322.
  • Kelly SD; Laney Graduate School, Emory University, Atlanta, Georgia 30322.
  • Chang J; Laney Graduate School, Emory University, Atlanta, Georgia 30322.
  • Bengoa-Vergniory N; Laney Graduate School, Emory University, Atlanta, Georgia 30322.
  • Wade-Martins R; Laney Graduate School, Emory University, Atlanta, Georgia 30322.
  • Giasson BI; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom.
  • Joers V; Oxford Parkinson's Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom.
  • Weinshenker D; Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, Florida 32610.
  • Tansey MG; Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, Florida 32610.
J Neurosci ; 40(39): 7559-7576, 2020 09 23.
Article en En | MEDLINE | ID: mdl-32868457
Degeneration of locus ceruleus (LC) neurons and dysregulation of noradrenergic signaling are ubiquitous features of Parkinson's disease (PD). The LC is among the first brain regions affected by α-synuclein (asyn) pathology, yet how asyn affects these neurons remains unclear. LC-derived norepinephrine (NE) can stimulate neuroprotective mechanisms and modulate immune cells, while dysregulation of NE neurotransmission may exacerbate disease progression, particularly nonmotor symptoms, and contribute to the chronic neuroinflammation associated with PD pathology. Although transgenic mice overexpressing asyn have previously been developed, transgene expression is usually driven by pan-neuronal promoters and thus has not been selectively targeted to LC neurons. Here we report a novel transgenic mouse expressing human wild-type asyn under control of the noradrenergic-specific dopamine ß-hydroxylase promoter (DBH-hSNCA). These mice developed oligomeric and conformation-specific asyn in LC neurons, alterations in hippocampal and LC microglial abundance, upregulated GFAP expression, degeneration of LC fibers, decreased striatal DA metabolism, and age-dependent behaviors reminiscent of nonmotor symptoms of PD that were rescued by adrenergic receptor antagonists. These mice provide novel insights into how asyn pathology affects LC neurons and how central noradrenergic dysfunction may contribute to early PD pathophysiology.SIGNIFICANCE STATEMENT ɑ-Synuclein (asyn) pathology and loss of neurons in the locus ceruleus (LC) are two of the most ubiquitous neuropathologic features of Parkinson's disease (PD). Dysregulated norepinephrine (NE) neurotransmission is associated with the nonmotor symptoms of PD, including sleep disturbances, emotional changes such as anxiety and depression, and cognitive decline. Importantly, the loss of central NE may contribute to the chronic inflammation in, and progression of, PD. We have generated a novel transgenic mouse expressing human asyn in LC neurons to investigate how increased asyn expression affects the function of the central noradrenergic transmission and associated behaviors. We report cytotoxic effects of oligomeric and conformation-specific asyn, astrogliosis, LC fiber degeneration, disruptions in striatal dopamine metabolism, and age-dependent alterations in nonmotor behaviors without inclusions.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Enfermedad de Parkinson / Locus Coeruleus / Alfa-Sinucleína / Neuronas Adrenérgicas / Gliosis Límite: Animals / Female / Humans / Male Idioma: En Revista: J Neurosci Año: 2020 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Enfermedad de Parkinson / Locus Coeruleus / Alfa-Sinucleína / Neuronas Adrenérgicas / Gliosis Límite: Animals / Female / Humans / Male Idioma: En Revista: J Neurosci Año: 2020 Tipo del documento: Article