Elevated Stimulatory and Reduced Inhibitory G Protein α Subunits in Cerebellar Cortex of Patients with Dominantly Inherited Olivopontocerebellar Atrophy

: Although guanine nucleotide binding proteins (G proteins) are one of the critical components of signal transduction units for various membrane receptor‐mediated responses, little information is available regarding their status in brain of patients with neurodegenerative illnesses. We measured the immunoreactivity of G protein subunits (Gsα, Giα, Goα, Gq/11α, and Gβ) in autopsied cerebellar and cerebral cortices of 10 end‐stage patients with dominantly inherited olivopontocerebellar atrophy (OPCA) who all had severe loss of Purkinje cell neurons and climbing fiber afferents in cerebellar cortex. Compared with the controls, the long‐form Gsα (52‐kDa species) immunoreactivity was significantly elevated by 52% (p < 0.01) in the cerebellar cortex of the OPCA patients, whereas the Gi1α concentration was reduced by 35% (p < 0.02). No statistically significant differences were observed for Goα, Gi2α, Gβ1, Gβ2, or Gq/11α in cerebellar cortex or for any G protein subunit in the two examined cerebral cortical subdivisions (frontal and occipital). The cerebellar Gsα elevation could represent a compensatory response (e.g., sprouting, reactive synaptogenesis) by the remaining cerebellar neurons (granule cells?) to neuronal damage but also might contribute to the degenerative process, as suggested by the ability of Gsα, in some experimental preparations, to promote calcium flux. Further studies will be required to determine the actual functional consequences of the G protein changes in OPCA and whether the elevated Gsα is specific to OPCA cerebellum, because of its unique cellular pattern of morphological damage, or is found in brain of patients with other progressive neurodegenerative disorders.