• Identification of ubiquilin, a novel presenilin interactor that modulates presenilin protein accumulation and enhances presenilin-induced cell death

      Mah, Alex Lee; Monteiro, Mervyn J. (2000)
      Mutations in the highly homologous presenilin genes encoding presenilin-1 and presenilin-2 (PS1 and PS2) are linked to early-onset familial Alzheimer's disease (FAD). However, apart from a role in early development, neither the normal function of the presenilins nor the mechanisms by which mutant proteins cause AD are well understood. We describe here the properties of a novel human interactor of the presenilins named ubiquilin. Yeast two-hybrid (Y2H) interactions, GST pull-down experiments, and colocalization of the proteins expressed in vivo, together with coimmunoprecipitation and cell fractionation studies, provide compelling evidence that ubiquilin interacts with both PS1 and PS2. Ubiquilin is noteworthy since it contains multiple ubiquitin-related domains typically thought to be involved in targeting proteins for degradation. However, we show that ubiquilin promotes presenilin protein accumulation, suggesting that it functions in promoting presenilin stability. While overexpression of ubiquilin by itself does not affect cell survival, when coexpressed with PS2, ubiquilin enhances cell death resulting from PS2 overexpression. Our studies suggest that ubiquilin is an important modulator of presenilin function. Moreover, immunostaining of tissue sections from AD brain, Parkinson's disease brain, and diffuse Lewy body disease brain revealed immunoreactive structures to anti-ubiquilin antibodies including senile plaques, Hirano bodies, and Lewy bodies. Since these diseases involve abnormally aggregated protein species, it raises the possibility of a link between ubiquilin and the protein folding or degradation pathways.