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.

Oligodendroglia and Myelin in Neurodegenerative Diseases: More Than Just Bystanders?

“…In contrast to motor dysfunction, nonmotor symptoms including impaired olfaction as well as cardiovascular and urogenital dysfunction are less mirrored in transgenic mice [188–192]. In the PLP-driven model, however, oligodendroglial lesions and neuronal cell loss were recently described in multiple regions controlling autonomic functions matching the occurrence of cardiovascular dysfunctions in this model [189, 193]. …”

Animal Models of Multiple-System Atrophy

“…In contrast to the motor disability that seems to get pronounced rather late in the individual life, autonomic features may occur earlier. Already, at 5 months of age, PLPaSyn mice show reduced heart rate variability in both time and frequency domains, indicative of changed sympathovagal balance similar to the human disease [33]. Even earlier, at 2 months of age, changes seem to be detected in the urinary bladder function related to detrusor-sphincter dyssynergia as indirectly suggested by the morphological changes of the bladder wall and progress to result in increased post-void residual volume [34].…”

“…Neuronal loss in central autonomic centers in the brain stem and the spinal cord of the PLP-aSyn mice appears much earlier than striatonigral pathology. Already, at 2 months of age, neurodegeneration can be detected in the intermediolateral columns of the spinal cord (the parasympathetic outflow), the laterodorsal tegmental nucleus, the pedunculopontine tegmental nucleus, and the Onuf's nucleus; at 5 months of age, neuronal loss can be detected in nucleus ambiguus, followed later on by the Barrington's nucleus, raphe obscurus and pallidus [33][34][35]39].…”

Distinct Parameters in the EEG of the PLP α-SYN Mouse Model for Multiple System Atrophy Reinforce Face Validity

“…Epidemiologic studies report a disease probability of 0.6–3/100.000 patients per year (Bower et al, 1997). The mean disease onset is around 60 years and both sexes are affected equally with less than 9 years survival time after onset (Schrag et al, 2008; Kuzdas et al, 2013). Ethnic differences exist in the expression of the motor sub-forms.…”

“…Behavioral phenotyping performed with this animal model revealed coherence with key symptoms of MSA in humans: Urodynamic analysis showed a less efficient and unstable bladder activity with an increased voiding contraction amplitude, a higher frequency of non-voiding contractions and an increased post-void residual volume (Boudes et al, 2013). Other non-motor symptoms were a decreased heart rate variability (Kuzdas et al, 2013) and respiratory dysfunction (Flabeau et al, 2014). The PLP α-SYN model also showed shorter stride length, deficits on pole rod and beam walking tests as well as changes in grip strength and gait variability (Stefanova et al, 2005a,b).…”