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Dominant negative mechanism of Presenilin-1 mutations in FAD

  1. Jie Shenb,1
  1. aDepartment of Physiology, Keio University School of Medicine, Tokyo, 160-8582, Japan;
  2. bDepartment of Neurology, Brigham & Women’s Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115

Alzheimer’s disease (AD) is the most common form of dementia, afflicting more than 5 million people in the United States alone. Mutations in the Presenilin genes (PSEN1 and PSEN2) are highly penetrant and account for ~90% of all mutations identified in familial AD (FAD), highlighting their importance in the pathogenesis of AD. The presenilin proteins (PS1 and PS2) are broadly expressed and serve as the catalytic subunit of the γ-secretase complex, an intramembranous aspartyl protease that cleaves a variety of type 1 transmembrane proteins, including the amyloid precursor protein (APP) and Notch. The β- and γ-secretase–mediated cleavages of APP release β-amyloid (Aβ) peptides of varying lengths and C-terminal heterogeneity. More than 200 distinct mutations in PSEN1 have been reported (www.alzforum.org), and they are dominantly inherited and mostly missense mutations. Despite extensive studies on the effects of PSEN1 mutations, the pathogenic mechanism is still being debated. In PNAS, Zhou et al. (1) take advantage of their expertise in expression and purification of γ-secretase complexes in vitro to evaluate the effects of PSEN1 mutations on the activity of γ-secretase containing wild-type PS1. Their findings show that γ-secretase complexes containing mutant PS1 exert dominant negative effects on wild-type γ-secretase in the production of Aβ, providing compelling evidence and further insight into how dominantly inherited missense mutations in PSEN1 impair γ-secretase activity and cause FAD.

The dominant negative mechanism of PSEN mutations in FAD was initially proposed by the presenilin hypothesis to explain the dominant inheritance and missense nature of large numbers of PSEN1 pathogenic mutations distributed throughout the coding sequence and the absence of pathogenic nonsense or frame-shift mutations (2). The presenilin hypothesis, which posits that PSEN mutations cause FAD via a loss of essential presenilin functions in the brain, was prompted by the age-dependent cortical neurodegeneration and dementia observed in Psen conditional …

?1To whom correspondence should be addressed. Email: jshen{at}bwh.harvard.edu.

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