FTLD疾患スペクトラムに共通する病態としてのFUS機能不全

Aberrant Interaction Between FUS and SFPQ in Neurons in a Wide Range of FTLD Spectrum Diseases

広義前頭側頭葉変性症（FTLD）疾患スペクトラム（筋萎縮性側索硬化症，FTLD，進行性核上性麻痺，大脳皮質基底核変性症）の神経細胞においてFUSとSFPQの核内での会合異常と，これらが制御するタウアイソフォームのバランス異常を見出した。こうした変化はアルツハイマー病やピック病では存在せず，広義FTLD疾患スペクトラム共通の病態であることが示唆された。

Abstract

Fused-in sarcoma (FUS) is genetically and clinicopathologically linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We have previously reported that intranuclear interactions of FUS and splicing factor, proline- and glutamine-rich (SFPQ) contribute to neuronal homeostasis. Under normal conditions, FUS forms a high-molecular-weight complex with SFPQ in the nucleus. However, disease-associated mutations in the FUS gene disrupt formation of the complex, resulting in unregulated alternative splicing of tau, a disproportional increase in the 4-repeat (4R)-tau/3-repeat (3R)-tau ratio, and eventual neurodegeneration. Disruption of the FUS-SFPQ interaction leads to an increase in the 4R-tau/3R-tau ratio, which manifests as FTLD-like phenotypes in mice. Here, we examined FUS-SFPQ interactions in 142 autopsied individuals with ALS/FTLD, progressive supranuclear palsy (PSP), cortico-basal degeneration (CBD), Alzheimer's disease (AD), or Pick's disease (PiD). Immunofluorescence imaging showed impaired intranuclear colocalization of FUS and SFPQ in the neurons in the ALS/FTLD, PSP, and CBD cases, but not in the AD and PiD cases. Furthermore, the ratio of 4R-tau/3R-tau was elevated in cases of ALS/FTLD and PSP but was largely unaffected in cases of AD. We concluded that impaired interactions between FUS and SFPQ and the subsequent increase in the 4R-tau/3R-tau ratio constitute a common pathogenesis pathway in FTLD spectrum diseases.