Upregulation of α-synuclein expression in the rat cerebellum in experimental hepatic encephalopathy

I. Suarez, G. Bodega and B. Fernandez (2010) Neuropathology and Applied Neurobiology36, 422–435 Upregulation of α-synuclein expression in the rat cerebellum in experimental hepatic encephalopathy Aims: The overexpression of α-synuclein has been associated with neurodegenerative diseases, especially when the protein aggregates to form insoluble structures. The present study examined the effect of chronic hyperammonaemia on α-synuclein expression in the rat cerebellum following portacaval anastomosis (PCA). Methods: Immunohistochemical and western blot determinations were performed 1 month and 6 months after the PCA procedure. Results: A time-dependent increase in α-synuclein expression was seen in the cerebellar grey matter compared with the controls. At 1 month post PCA, α-synuclein-immunopositive material was observed in the molecular layer, while the Purkinje cells showed weak α-synuclein expression, and α-synuclein aggregates were observed throughout the granular layer. At 6 months post PCA, α-synuclein expression was significantly increased compared with the controls. α-synuclein-immunostained astroglial cells were also found; the Bergmann glial cells showed α-synuclein-positive processes in the molecular layer of PCA-exposed rats, and in the granular layer, perivascular astrocytes showed intense α-synuclein immunoreactivity, as indicated by colocalization of α-synuclein with glial fibrillary acidic protein (GFAP). In addition, ubiquitin-immunoreactive inclusions were present in PCA-exposed rats, although they did not colocalize with α-synuclein. Western blotting performed at 6 months post PCA showed a reduction in the level of soluble α-synuclein compared with 1 month post PCA and the controls; this reduction was concomitant with an increase in the insoluble form of α-synuclein. Conclusions: Although the precise mechanism by which α-synuclein aggregates in PCA-treated rats remains unknown, the present data suggest an important role for this protein in the onset and progression of hepatic encephalopathy, probably via its expression in astroglial cells.