Huntington's disease: changes in striatal proteins reflect astrocytic gliosis

Huntington's disease is an autosomal dominant neuronal degeneration characterized by age-related neuronal loss principally affecting caudate and putamen and, to a lesser extent, cerebral cortex. In order to identify selective polypeptide alterations in HD brain, we analyzed unfractionated homogenates and purified neuronal perikarya from striatum and cortex of 12 control and 14 HD brains by gel electrophoresis and immunochemical techniques. SDS polyacrylamide gel electrophoresis (SDS-PAGE) revealed a 3- to 8-fold increase in a 50,000 MW (50K) protein in HD striatal homogenates. Neuronal fractions isolated from the same tissue almost never showed this change. In cortex, 50 K protein was either normal or minimally increased. The increase at 50 K in striatal homogenates was often associated with variable increases of proteins at 40 K and 43 K. No other consistent polypeptide changes in HD brain tissue were found by one-dimensional SDS-PAGE. The increased 40 K protein in HD striatum extracts showed a strong immunoprecipitant line with an antiserum to GFA. This antiserum also produced greater immunofluorescent staining of HD than control striatum. Direct immunostaining of polypeptides in gels demonstrated selective staining of the 50 K, 43 K and 40 K proteins in HD striatum. The pattern was highly similar to that reported by Dahl et al. 6 for glial filament preparations that underwent postmortem proteolysis. We conclude that these polypeptide changes are related to increased glial filaments in affected HD tissue, and that similar protein changes reported in other human neuronal degenerations also reflect secondary astrocytic gliosis rather than the primary gene product.