title: Oligodendroglial alpha-synucleinopathy and MSA-like cardiovascular autonomic failure: experimental evidence.
abstract: Multiple system atrophy (MSA) is a fatal, rapidly progressive neurodegenerative disease with limited symptomatic treatment options. Discrimination of MSA from other degenerative disorders crucially depends on the presence of early and severe cardiovascular autonomic failure (CAF). We have previously shown that neuropathologic lesions in the central autonomic nuclei similar to the human disease are present in transgenic MSA mice generated by targeted oligodendroglial overexpression of α-syn using the PLP promoter. We here explore whether such lesions result in abnormalities of heart rate variability (HRV) and circadian rhythmicity which are typically impaired in MSA patients. HRV analysis was performed in five month old transgenic PLP-α-syn (tg) MSA mice and age-matched wild type controls. Decreased HRV and alterations in the circadian rhythmicity were detected in the tg MSA group. The number of choline-acetyltransferase-immunoreactive neurons in the nucleus ambiguus was significantly decreased in the tg group, whereas the levels of arginine-vasopressin neurons in the suprachiasmatic and paraventricular nucleus were not affected. Our finding of impaired HRV and circadian rhythmicity in tg MSA mice associated with degeneration of the nucleus ambiguus suggests that a cardinal non-motor feature of human MSA can be reproduced in the mouse model strengthening its role as a valuable testbed for studying selective vulnerability and assessing translational therapies.
authors: Division of Neurobiology, Department of Neurology and Neurosurgery, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
authors: Daniela
authors: D
authors: Kuzdas
authors: Sylvia
authors: S
authors: Stemberger
authors: Stefano
authors: S
authors: Gaburro
authors: Nadia
authors: N
authors: Stefanova
authors: Nicolas
authors: N
authors: Singewald
authors: Gregor K
authors: GK
authors: Wenning
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism; D001831:Body Temperature / Q000235:genetics; D018376:Cardiovascular Abnormalities / Q000209:etiology* / Q000235:genetics; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D004569:Electroencephalography; D006339:Heart Rate / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D019578:Multiple System Atrophy / Q000150:complications* / Q000235:genetics; D018991:Myelin Proteolipid Protein / Q000235:genetics; D009714:Nucleus Accumbens / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018991:Myelin Proteolipid Protein; D051844:alpha-Synuclein; D001127:Arginine Vasopressin; D002795:Choline O-Acetyltransferase
keywords: (oligodendro-)glial cytoplasmic inclusions; AVP; Alpha-synuclein; Autonomic failure; ChAT; ECG; GCI; HF; Heart rate variability; LF; MR; MSA; MSA-C; MSA-P; Multiple system atrophy; OPCA; PET; PLP; RMSSD; SAOA; SND; SPECT; TH; Transgenic animal model; UMSARS; alpha-synuclein; arginine-vasopressin; cerebellar variant of MSA; choline-acetyltransferase; electrocardiogram; high frequency; low frequency; magnetic resonance; multiple system atrophy; olivopontocerebellar atrophy; parkinsonian variant of MSA; positron emission tomography; proteolipid protein promoter; root mean square of successive RR interval differences; single-photon emission computed tomography; sporadic adult onset ataxia; striatonigral degeneration; tg; transgenic; tyrosine hydroxylase; unified MSA rating scale; wild type; wt; α-syn
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