FUS-lmmunoreactive Intranuclear Inclusions in Neurodegenerative Disease

摘要

Neuronal intranuclear inclusions (Nils) are a histopathological hallmark of several neurodegenerative disorders. However, the role played by Nils in neurodegenerative pathogenesis remains enigmatic. Defining their molecular composition represents an important step in understanding the pathophysiology of these disorders. Recently, a nuclear protein, "fused-in-sarcoma" (FUS) was identified as the pathological protein in two forms of frontotemporal lobar degeneration (FTLD-IF, formerly known as neuronal intermediate filament inclusion disease, and FTLD-UPS, formerly known as atypical FTLD-U), both of which are characterized by the presence of NIL The obj ective of the present study was to determine the range of neurodegenerative disorders characterized by FUS-positive Nils. Immunostaining for FUS revealed intense reactivity of Nils in FTLD-IF and FTLD-UPS as well as in Hunting-ton's disease, spinocerebellar ataxias 1 and 3, and neuronal intranuclear inclusion body disease. In contrast, there was no FUS staining of Nils in inherited forms of FTLD-TDP caused by GRN and VCP mutations, fragile-X-associated tremor ataxia syndrome, or oculo-pharyngeal muscular dystrophy. In a cell culture model of Huntington's disease, Nils were intensely FUS-positive. Nil-bearing cells displayed loss of the normal diffuse nuclear pattern of FUS staining. This suggests that sequestration of nuclear FUS by Nils may interfere with its normal nuclear localization.