Abstract

Multiple system atrophy (MSA) is a fatal, rapidly progressive neurodegenerative disease with (oligodendro-)glial cytoplasmic α-synuclein (α-syn) inclusions (GCIs). Peripheral neuropathies have been reported in up to 40% of MSA patients, the cause remaining unclear. In a transgenic MSA mouse model featuring GCI-like inclusion pathology based on PLP-promoter driven overexpression of human α-syn in oligodendroglia motor and non-motor deficits are associated with MSA-like neurodegeneration. Since α-syn is also expressed in Schwann cells we aimed to investigate whether peripheral nerves are anatomically and functionally affected in the PLP-α-syn MSA mouse model.ResultsTo this end, heat/cold as well as mechanical sensitivity tests were performed. Furthermore, in vivo and ex vivo nerve conduction and the G-ratios of the sciatic nerve were analyzed, and thermosensitive ion channel mRNA expression in dorsal root ganglia (DRG) was assessed. The presence of human α-syn in Schwann cells was associated with subtle behavioral impairments. The G-ratio of the sciatic nerve, the conduction velocity of myelinated and unmyelinated primary afferents and the expression of thermosensitive ion channels in the sensory neurons, however, were similar to wildtype mice.ConclusionOur results suggest that the PNS appears to be affected by Schwann cell α-syn deposits in the PLP-α-syn MSA mouse model. However, there was no consistent evidence for functional PNS perturbations resulting from such α-syn aggregates suggesting a more central cause of the observed behavioral abnormalities. Nonetheless, our results do not exclude a causal role of α-syn in the pathogenesis of MSA associated peripheral neuropathy.

Highlights

  • Multiple system atrophy is a fatal, sporadic, adult-onset, neurodegenerative disease, characterized by parkinsonism, cerebellar ataxia, and autonomic failure (AF) in different combinations [1, 2]

  • The presence of human α-syn in Schwann cells was associated with subtle behavioral impairments

  • Our results suggest that the peripheral nervous system (PNS) appears to be affected by Schwann cell α-syn deposits in the proteolipid protein (PLP)-α-syn Multiple system atrophy (MSA) mouse model

Read more

Summary

Introduction

Multiple system atrophy is a fatal, sporadic, adult-onset, neurodegenerative disease, characterized by parkinsonism, cerebellar ataxia, and autonomic failure (AF) in different combinations [1, 2]. The mean age of disease onset is around 56 years and survival after disease onset lies between 6 and 9 years [3]. The prevalence is 1.9–4.9/100,000 and the incidence is 3/100,000/ year in the population over 50 years, MSA meets orphan-disease status (Orpha number: ORPHA102)[4]. Depending on the predominant motor presentation, MSA can be classified into a Parkinson variant (MSA-P) associated with striatonigral degeneration (SND) and a cerebellar variant (MSA-C) defined by olivopontocerebellar atrophy (OPCA)[5]. In PD and DLB, α-syn-positive aggregates are mainly found in neurons, whereas the predominant location for α-syn accumulation in MSA is the cytoplasm of oligodendrocytes forming glial cytoplasmic inclusions (GCIs) [6]

Objectives
Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call