60
C. Haass
complex formation composed of NTF and CTF may be required for the
activity of PS proteins, a hypothesis which is strongly supported by the
recently identified dominant negative mutations described below.
4.4 Presenilins Facilitate A~ Production
Besides the pathological function of mutant PS in A~42 generation,
wild-type PS proteins appear to have a fundamental function in physiological A~ production, since it was recently found that PS 1- 1 - mice
produce significantly reduced amounts of A~40 and A~42 (De Strooper
et al. 1998). Since C-terminal fragments of ~APP accumulate in neurons
derived from the brains of PS-I- mice, it has been proposed that PS
proteins may either activate y-secretase (De Strooper et al. 1998; Haass
and Selkoe 1998) or may even exhibit a y-secretase activity by themselves. This proposal is based on the identification of two unusual
intramembranous aspartate residues within transmembrane domains 6
and 7 (Wolfe et al. 1999; Fig. 1). Strikingly, when these aspartates were
mutagenized the resulting PS variants completely blocked endoproteolysis of PS 1. This was accompanied by a pronounced decrease in
both major A~ species, A~40 and A~42' Moreover, C-terminal fragments
of ~APP produced either by (X- or ~-secretase accumulated to high
levels. This indicates a major defect in the y-secretase activity that would
normally process these fragments to A~ and p3, and hence the aspartate
mutants have a dominant negative effect on y-secretase activity. These
findings are strikingly similar to the effects of a PS 1 knockout in mice
described above. The critical aspartate residues of PS 1 are functionally
conserved in human PS2 (Steiner and Haass, submitted) and zebrafish
PS 1 (Leimer and Haass, submitted). Based on these recent findings,
Selkoe and colleagues presented a very exciting model in which PS
proteins are unusual aspartyl proteases, and are in fact the long-sought
y-secretase (Fig. 1). Aspartyl proteases require two aspartate residues
within their enzymatically active domain. Mutagenizing either one of
them results in a complete loss of proteolytic activity. Therefore, presenilins may be autocatalytic ally activated, cleaving ~APP within the
membrane to generate A~ and p3 (Fig. 1).
C. Haass
complex formation composed of NTF and CTF may be required for the
activity of PS proteins, a hypothesis which is strongly supported by the
recently identified dominant negative mutations described below.
4.4 Presenilins Facilitate A~ Production
Besides the pathological function of mutant PS in A~42 generation,
wild-type PS proteins appear to have a fundamental function in physiological A~ production, since it was recently found that PS 1- 1 - mice
produce significantly reduced amounts of A~40 and A~42 (De Strooper
et al. 1998). Since C-terminal fragments of ~APP accumulate in neurons
derived from the brains of PS-I- mice, it has been proposed that PS
proteins may either activate y-secretase (De Strooper et al. 1998; Haass
and Selkoe 1998) or may even exhibit a y-secretase activity by themselves. This proposal is based on the identification of two unusual
intramembranous aspartate residues within transmembrane domains 6
and 7 (Wolfe et al. 1999; Fig. 1). Strikingly, when these aspartates were
mutagenized the resulting PS variants completely blocked endoproteolysis of PS 1. This was accompanied by a pronounced decrease in
both major A~ species, A~40 and A~42' Moreover, C-terminal fragments
of ~APP produced either by (X- or ~-secretase accumulated to high
levels. This indicates a major defect in the y-secretase activity that would
normally process these fragments to A~ and p3, and hence the aspartate
mutants have a dominant negative effect on y-secretase activity. These
findings are strikingly similar to the effects of a PS 1 knockout in mice
described above. The critical aspartate residues of PS 1 are functionally
conserved in human PS2 (Steiner and Haass, submitted) and zebrafish
PS 1 (Leimer and Haass, submitted). Based on these recent findings,
Selkoe and colleagues presented a very exciting model in which PS
proteins are unusual aspartyl proteases, and are in fact the long-sought
y-secretase (Fig. 1). Aspartyl proteases require two aspartate residues
within their enzymatically active domain. Mutagenizing either one of
them results in a complete loss of proteolytic activity. Therefore, presenilins may be autocatalytic ally activated, cleaving ~APP within the
membrane to generate A~ and p3 (Fig. 1).