Involvement of Peripheral Nerves in the Transgenic PLP-α-Syn Model of Multiple System Atrophy: Extending the Phenotype.
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.


RESULTS
To 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.


CONCLUSIONS
Our 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.
Department of Neurology, Medical University of Innsbruck, Innsbruck, Tirol, Austria.
Daniela
D
Kuzdas-Wood
Department of Anatomy, Histology and Embryology, Division of Clinical and Functional Anatomy, Medical University of Innsbruck, 6020 Innsbruck, Austria; Department of Anatomy, Histology and Embryology, Division of Neuroanatomy, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Regina
R
Irschick
Department of Cardiology and Angiology, Medical University of Innsbruck, Innsbruck, Tirol, Austria.
Markus
M
Theurl
Department of Physiology and Medical Physics, Medical University of Innsbruck, Innsbruck, Tirol, Austria.
Philipp
P
Malsch
Department of Physiology and Medical Physics, Medical University of Innsbruck, Innsbruck, Tirol, Austria.
Norbert
N
Mair
Department of Neurology, Medical University of Innsbruck, Innsbruck, Tirol, Austria.
Christine
C
Mantinger
Department of Neurology, Medical University of Innsbruck, Innsbruck, Tirol, Austria.
Julia
J
Wanschitz
Department of Anatomy, Histology and Embryology, Division of Clinical and Functional Anatomy, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Lars
L
Klimaschewski
Department of Neurology, Medical University of Innsbruck, Innsbruck, Tirol, Austria.
Werner
W
Poewe
Department of Neurology, Medical University of Innsbruck, Innsbruck, Tirol, Austria.
Nadia
N
Stefanova
Department of Neurology, Medical University of Innsbruck, Innsbruck, Tirol, Austria.
Gregor K
GK
Wenning
D000818:Animals; D001522:Behavior, Animal; D003080:Cold Temperature; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006358:Hot Temperature; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D019578:Multiple System Atrophy / Q000473:pathology* / Q000503:physiopathology; D018991:Myelin Proteolipid Protein / Q000235:genetics*; D009431:Neural Conduction; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism; D012584:Sciatic Nerve / Q000473:pathology*; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
D018991:Myelin Proteolipid Protein; D012333:RNA, Messenger; C497604:SNCA protein, human; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D051844:alpha-Synuclein