Novel intracytoplasmic inclusions immunoreactive for phosphorylated-TDP43 and cystatin C in anterior horn cells in a case of sporadic amyotrophic lateral sclerosis.

Novel intracytoplasmic inclusions immunoreactive for phosphorylated transactivation response DNA-binding protein 43 (p-TDP43), cystatin C, and transferrin were found in anterior horn cells in a case of sporadic amyotrophic lateral sclerosis (ALS). The patient was a 59-year-old woman, who died of ALS after a clinical course of 8 years. She had been receiving mechanical support for respiration for 6 years and in a "totally locked-in" state for 4 years prior to death. The spinal cord showed severe degeneration involving the anterior and lateral funiculi, whereas the posterior funiculus was preserved. Neurons in the anterior horn and Clarke's column were markedly lost, and many Bunina bodies and a few skein-like inclusions were found. Some remaining anterior horn cells had round and densely eosinophilic or amphophilic intracytoplasmic inclusions. They were immunoreactive for ubiquitin, p-TDP43, cystatin C and transferrin. On confocal laser microscopy, cystatin C was found to consistently surround p-TDP43 within the inclusions. The inclusions ultrastructurally consisted of granule-associated fibrils and, in the central portion, dense aggregates of fibrils were associated with masses of electron-dense, coarsely granular or amorphous material. Although their pathogenesis remains unknown, these unique inclusions may have been formed under a specific condition whereby p-TDP43 and cystatin C interacted with each other.