Striatal transplantation for multiple system atrophy — Are grafts affected by α-synucleinopathy?

Abstract

Multiple system atrophy (MSA), a fatal neurodegenerative disorder, is the second most common cause of parkinsonism and frequently associated with autonomic failure. Previous work from our laboratory has shown that striatal grafts survive and exert functional effects in toxin-induced rodent models of MSA-P, the parkinson variant characterized by levodopa resistance due to loss of striatal medium-sized spiny neurons. It is unknown whether oligodendroglial α-synuclein signature lesions affect graft survival in MSA. Recent reports on neurotransplantation in Parkinson's disease patients suggest a possible host-to-graft disease propagation of α-synuclein pathology which may be relevant to transplantation in MSA as well. We here demonstrate that embryonic E14 striatal allografts show reduced p-zone volume and dopaminergic graft re-innervation accompanied by increased gliosis in a transgenic MSA mouse model featuring α-synuclein oligodendrogliopathy. Oligodendrocytes expressing host-specific α-synuclein migrate into the graft tissue after 3 months of survival. Our data suggest that the presence of MSA-like α-synuclein oligodendrogliopathy and related to it pro-inflammatory microenvironment may compromise the connectivity and neurorestorative outcome of striatal grafts.