Age and Gender Differences in Cardiovascular Autonomic Failure in the Transgenic PLP-syn Mouse, a Model of Multiple System Atrophy

Abstract

Multiple system atrophy (MSA) is a rare and progressive neurodegenerative disorder. Autonomic failure (AF) is one main clinical feature which has a significant impact on health-related quality of life. The neuropathological hallmark of MSA is the abnormal accumulation of α-synuclein in oligodendrocytes forming glial cytoplasmic inclusions. Only little is known about gender and age differences in AF in MSA. This study was carried out in 6 and 12 months old transgenic PLP-α-syn and WT male and female mice. Heart rate variability (HRV) was assessed both in time, frequential and non-linear domains. Baroreflex sensitivity (BRS) was estimated by the sequence method. Duration of ventricular depolarization and repolarization (QT/QTc intervals) were evaluated from the ECG signals. Three-way ANOVA (genotype x gender x age) with Sidak's method post-hoc was used to analyze data. BRS was significantly changed in PLP-α-syn mice and was age-dependent. QT and QTc intervals were not significantly modified in PLP-α-syn mice. An impaired HRV was observed at 12 months of age in PLP-α-syn female but not in male mice, indicative of cardiovascular AF.

Relationship among α‑synuclein, aging and inflammation in Parkinson's disease (Review)

“…Oligodendrocytes are glial cells of the CNS that possess numerous functions, including myelin generation, metabolic support, immunomodulation and production of neurotrophins, such as glial cell line-derived neurotrophic factor, BDNF and IGF-1 ( 73 , 103 ).…”

“…The amount of endogenous α-Syn protein expressed by rat oligodendrocyte lineage cells is ~20% of that expressed by neurons ( 104 ). In multiple system atrophy (MSA), a rare neurodegenerative disorder, pathological α-Syn accumulates in oligodendrocytes, forming glial cytoplasmic inclusions (GCIs), which is a unique hallmark of this disease ( 31 , 103 ). In PD, by contrast, misfolded α-Syn mainly appears in neurons ( 105 ), forming LNs and LBs.…”

“…In AON regions of postmortem patients with PD, α-Syn is present in some neurons, astrocytes, microglia and pericytes, whereas no α-Syn is present in oligodendrocytes ( 5 ). In MSA, oligodendrocytes are affected by α-Syn and α-Syn aggregates to form GCIs, while in PD, α-Syn mainly affects neurons and aggregates to form LNs and LBs ( 2 , 3 , 31 , 103 , 105 ). This is a future research direction which requires further study, as related studies may be of significance for revealing the toxicity of α-Syn and the pathogenesis of synucleinopathies, including MSA and PD.…”