Fig. 1.

Neuropathology of c9RAN poly(GA) proteins in C9ORF72 repeat expansion cases. a–f Immunohistochemical analysis shows that poly(GA) proteins accumulate throughout the central nervous system of C9ORF72 repeat expansion carriers as neuronal cytoplasmic inclusions and neuronal intranuclear inclusions (arrow in insert, a). Regions with a particularly high burden include the dentate fascia of the hippocampus (a; Case 8), the hippocampus proper (b; CA3/2; Case 10), the anterior thalamus (c; Case 4), the frontal cortex (d; Layers IV–V; Case 7), the cerebellar molecular layer (e; Case 1) and the cerebellar internal granule cell layer (f; Case 9). Scale bar represents 25 µm (a–e) and 20 µm (f). Regular electron microscopy (EM) of granule cells of the cerebellar cortex from a c9FTD-MND case shows that cytoplasmic inclusions (g) are composed of 15–17 nm filaments (arrow, h). Immuno-EM with anti-poly(GA) antibody labeled with gold particles (18 nm) reveals poly(GA) proteins localize to filaments (arrow, i). Scale bars represent 0.5 μm (g), 100 nm (h), and 50 nm (i). j Dot blot reveals that anti-poly(GA) immunoreactivity in cerebellar urea fractions is specific to c9FTD/ALS. Each dot represents one case