Checler F, Afram E, Pardossi-Piquard R, Lauritzen I.
Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?.
J Biol Chem. 2021 Jan-Jun;296:100489. Epub 2021 Mar 1
PubMed.
Checler et al. have published a very informative review of the evidence that the precursor to Aβ, the “βCTF” or “C99” fragment of APP, is likely a very important (if not the most important) derivative of APP acting in the pathogenic process leading to Alzheimer’s disease. The authors have done a wonderful job of collecting a great many various lines of evidence into their paper. There are a few points I would like to make in association with this:
1) The authors rightly point out that much of the genetic evidence from fAD mutations identified in APP is consistent with a pathogenic role for increased C99 formation. I think that this provides a more parsimonious explanation for the pathogenic effect of these mutations than qualitative changes in the form of Aβ.
2) The idea that C99 is a (or the) pathogenic agent resulting from fAD mutations in APP is not actually inconsistent with the Amyloid Cascade Hypothesis as originally described. In their 1992 paper declaring the hypothesis (Hardy et al., 1992), Hardy and Higgins wrote, “Our cascade hypothesis states that AβP itself, or APP cleavage products containing AβP, are neurotoxic and lead to neurofibrillary tangle formation and cell death.”
3) The authors describe two main hypotheses regarding the effects of fAD mutations in the presenilin genes: gain-of-function and loss-of-function of γ-secretase. Of course, loss-of-function is consistent with accumulation of C99 and the authors rightly point to the study of 138 fAD mutations of PSEN1 by Sun et al. (Sun et al., 2017) as demonstrating that 90 percent of the mutations do show reduced γ-secretase activity (cleavage of C99) in in vitro studies. However, they are incorrect in reporting that the Sun et al. paper showed these mutations as acting in a dominant negative manner. It was Heilig et al. (Heilig et al., 2013) with Shen and Kelleher who first demonstrated the dominant negative effect, but they only examined mutations causing reduced γ-secretase activity. Although Kelleher and Shen (Kelleher and Shen, 2017) claimed, regarding Sun et al.’s work, that “their results point to loss of γ-secretase activity as the primary molecular defect imposed by pathogenic PSEN1 mutations” this ignores the fact that ~10 percent of the mutations analysed by Sun et al. (at least 11 mutations) caused increased γ-secretase cleavage of C99. Independent confirmation of increased γ-secretase activity for one of these mutations has been provided by Zhou et al. (Zhou et al., 2017) (for PSEN1 S365A). Any unified explanation for the action of fAD mutations in the presenilin genes cannot ignore these numerous mutations that appear to increase γ-secretase activity. The one universally consistent phenomenon for the presenilin mutations causing fAD is that these always cause production of at least one transcript isoform preserving the original open reading frame (i.e., allowing translation of a “full-length” protein). We have previously described this as the “reading frame preservation rule.” As we noted previously (Jayne et al., 2016), a case can be made that the fAD-causative effect of presenilin mutations is expressed through their effect on the function of the presenilin holoprotein, an idea that is consistent with the reading frame preservation rule and the observations of the Nixon laboratory (Lee et al., 2010) that fAD mutations disrupt lysosomal acidification by a γ-secretase-independent effect on holoprotein function. One possibility (among others requiring testing) for a unified effect of presenilin fAD mutations is that their deleterious effects on endolysosomal acidification in vivo may reduce γ-secretase activity to the extent that this overwhelms any increased intrinsic γ-secretase activity of a mutant enzyme complex (since normal endolysosomal acidification appears important for γ-secretase cleavage of Notch (Valapala et al., 2013; Yan et al., 2009) and so might similarly affect C99).
4) Lastly, the accumulation of Aβ in brains has been viewed as “toxic” since, for many years, Aβ was not thought to fulfill any pro-survival purpose. This also made Aβ an acceptable target for drugs blocking its supposedly toxic action. However, it would be unfortunate if C99 was also perceived this way (by being thought of as “toxic”). The work of Pera et al. (Pera et al., 2017), Jiang et al. (Jiang et al., 2019), Montesinos et al. (Montesinos et al., 2020) and others clearly demonstrates that C99 has important roles in cell physiology and that it would likely be unwise to inhibit completely its action in cells rather than modulating it.
Sun L, Zhou R, Yang G, Shi Y.
Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase.
Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5
PubMed.
Heilig EA, Gutti U, Tai T, Shen J, Kelleher RJ.
Trans-dominant negative effects of pathogenic PSEN1 mutations on γ-secretase activity and Aβ production.
J Neurosci. 2013 Jul 10;33(28):11606-17.
PubMed.
Kelleher RJ 3rd, Shen J.
Presenilin-1 mutations and Alzheimer's disease.
Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):629-631. Epub 2017 Jan 12
PubMed.
Zhou R, Yang G, Shi Y.
Dominant negative effect of the loss-of-function γ-secretase mutants on the wild-type enzyme through heterooligomerization.
Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):12731-12736. Epub 2017 Oct 9
PubMed.
Jayne T, Newman M, Verdile G, Sutherland G, Münch G, Musgrave I, Moussavi Nik SH, Lardelli M.
Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer's Disease.
J Alzheimers Dis. 2016 Apr 4;52(3):781-99.
PubMed.
Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM, Martinez-Vicente M, Massey AC, Sovak G, Uchiyama Y, Westaway D, Cuervo AM, Nixon RA.
Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations.
Cell. 2010 Jun 25;141(7):1146-58.
PubMed.
Valapala M, Hose S, Gongora C, Dong L, Wawrousek EF, Samuel Zigler J Jr, Sinha D.
Impaired endolysosomal function disrupts Notch signalling in optic nerve astrocytes.
Nat Commun. 2013;4:1629.
PubMed.
Yan Y, Denef N, Schüpbach T.
The vacuolar proton pump, V-ATPase, is required for notch signaling and endosomal trafficking in Drosophila.
Dev Cell. 2009 Sep;17(3):387-402.
PubMed.
Pera M, Larrea D, Guardia-Laguarta C, Montesinos J, Velasco KR, Agrawal RR, Xu Y, Chan RB, Di Paolo G, Mehler MF, Perumal GS, Macaluso FP, Freyberg ZZ, Acin-Perez R, Enriquez JA, Schon EA, Area-Gomez E.
Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease.
EMBO J. 2017 Nov 15;36(22):3356-3371. Epub 2017 Oct 10
PubMed.
Jiang Y, Sato Y, Im E, Berg M, Bordi M, Darji S, Kumar A, Mohan PS, Bandyopadhyay U, Diaz A, Cuervo AM, Nixon RA.
Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99).
J Neurosci. 2019 Jul 3;39(27):5255-5268. Epub 2019 May 1
PubMed.
Montesinos J, Pera M, Larrea D, Guardia-Laguarta C, Agrawal RR, Velasco KR, Yun TD, Stavrovskaya IG, Xu Y, Koo SY, Snead AM, Sproul AA, Area-Gomez E.
The Alzheimer's disease-associated C99 fragment of APP regulates cellular cholesterol trafficking.
EMBO J. 2020 Oct 15;39(20):e103791. Epub 2020 Aug 31
PubMed.
Comments
The University of Adelaide
Checler et al. have published a very informative review of the evidence that the precursor to Aβ, the “βCTF” or “C99” fragment of APP, is likely a very important (if not the most important) derivative of APP acting in the pathogenic process leading to Alzheimer’s disease. The authors have done a wonderful job of collecting a great many various lines of evidence into their paper. There are a few points I would like to make in association with this:
1) The authors rightly point out that much of the genetic evidence from fAD mutations identified in APP is consistent with a pathogenic role for increased C99 formation. I think that this provides a more parsimonious explanation for the pathogenic effect of these mutations than qualitative changes in the form of Aβ.
2) The idea that C99 is a (or the) pathogenic agent resulting from fAD mutations in APP is not actually inconsistent with the Amyloid Cascade Hypothesis as originally described. In their 1992 paper declaring the hypothesis (Hardy et al., 1992), Hardy and Higgins wrote, “Our cascade hypothesis states that AβP itself, or APP cleavage products containing AβP, are neurotoxic and lead to neurofibrillary tangle formation and cell death.”
3) The authors describe two main hypotheses regarding the effects of fAD mutations in the presenilin genes: gain-of-function and loss-of-function of γ-secretase. Of course, loss-of-function is consistent with accumulation of C99 and the authors rightly point to the study of 138 fAD mutations of PSEN1 by Sun et al. (Sun et al., 2017) as demonstrating that 90 percent of the mutations do show reduced γ-secretase activity (cleavage of C99) in in vitro studies. However, they are incorrect in reporting that the Sun et al. paper showed these mutations as acting in a dominant negative manner. It was Heilig et al. (Heilig et al., 2013) with Shen and Kelleher who first demonstrated the dominant negative effect, but they only examined mutations causing reduced γ-secretase activity. Although Kelleher and Shen (Kelleher and Shen, 2017) claimed, regarding Sun et al.’s work, that “their results point to loss of γ-secretase activity as the primary molecular defect imposed by pathogenic PSEN1 mutations” this ignores the fact that ~10 percent of the mutations analysed by Sun et al. (at least 11 mutations) caused increased γ-secretase cleavage of C99. Independent confirmation of increased γ-secretase activity for one of these mutations has been provided by Zhou et al. (Zhou et al., 2017) (for PSEN1 S365A). Any unified explanation for the action of fAD mutations in the presenilin genes cannot ignore these numerous mutations that appear to increase γ-secretase activity. The one universally consistent phenomenon for the presenilin mutations causing fAD is that these always cause production of at least one transcript isoform preserving the original open reading frame (i.e., allowing translation of a “full-length” protein). We have previously described this as the “reading frame preservation rule.” As we noted previously (Jayne et al., 2016), a case can be made that the fAD-causative effect of presenilin mutations is expressed through their effect on the function of the presenilin holoprotein, an idea that is consistent with the reading frame preservation rule and the observations of the Nixon laboratory (Lee et al., 2010) that fAD mutations disrupt lysosomal acidification by a γ-secretase-independent effect on holoprotein function. One possibility (among others requiring testing) for a unified effect of presenilin fAD mutations is that their deleterious effects on endolysosomal acidification in vivo may reduce γ-secretase activity to the extent that this overwhelms any increased intrinsic γ-secretase activity of a mutant enzyme complex (since normal endolysosomal acidification appears important for γ-secretase cleavage of Notch (Valapala et al., 2013; Yan et al., 2009) and so might similarly affect C99).
4) Lastly, the accumulation of Aβ in brains has been viewed as “toxic” since, for many years, Aβ was not thought to fulfill any pro-survival purpose. This also made Aβ an acceptable target for drugs blocking its supposedly toxic action. However, it would be unfortunate if C99 was also perceived this way (by being thought of as “toxic”). The work of Pera et al. (Pera et al., 2017), Jiang et al. (Jiang et al., 2019), Montesinos et al. (Montesinos et al., 2020) and others clearly demonstrates that C99 has important roles in cell physiology and that it would likely be unwise to inhibit completely its action in cells rather than modulating it.
References:
Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992 Apr 10;256(5054):184-5. PubMed.
Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
Heilig EA, Gutti U, Tai T, Shen J, Kelleher RJ. Trans-dominant negative effects of pathogenic PSEN1 mutations on γ-secretase activity and Aβ production. J Neurosci. 2013 Jul 10;33(28):11606-17. PubMed.
Kelleher RJ 3rd, Shen J. Presenilin-1 mutations and Alzheimer's disease. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):629-631. Epub 2017 Jan 12 PubMed.
Zhou R, Yang G, Shi Y. Dominant negative effect of the loss-of-function γ-secretase mutants on the wild-type enzyme through heterooligomerization. Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):12731-12736. Epub 2017 Oct 9 PubMed.
Jayne T, Newman M, Verdile G, Sutherland G, Münch G, Musgrave I, Moussavi Nik SH, Lardelli M. Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer's Disease. J Alzheimers Dis. 2016 Apr 4;52(3):781-99. PubMed.
Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM, Martinez-Vicente M, Massey AC, Sovak G, Uchiyama Y, Westaway D, Cuervo AM, Nixon RA. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 2010 Jun 25;141(7):1146-58. PubMed.
Valapala M, Hose S, Gongora C, Dong L, Wawrousek EF, Samuel Zigler J Jr, Sinha D. Impaired endolysosomal function disrupts Notch signalling in optic nerve astrocytes. Nat Commun. 2013;4:1629. PubMed.
Yan Y, Denef N, Schüpbach T. The vacuolar proton pump, V-ATPase, is required for notch signaling and endosomal trafficking in Drosophila. Dev Cell. 2009 Sep;17(3):387-402. PubMed.
Pera M, Larrea D, Guardia-Laguarta C, Montesinos J, Velasco KR, Agrawal RR, Xu Y, Chan RB, Di Paolo G, Mehler MF, Perumal GS, Macaluso FP, Freyberg ZZ, Acin-Perez R, Enriquez JA, Schon EA, Area-Gomez E. Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO J. 2017 Nov 15;36(22):3356-3371. Epub 2017 Oct 10 PubMed.
Jiang Y, Sato Y, Im E, Berg M, Bordi M, Darji S, Kumar A, Mohan PS, Bandyopadhyay U, Diaz A, Cuervo AM, Nixon RA. Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99). J Neurosci. 2019 Jul 3;39(27):5255-5268. Epub 2019 May 1 PubMed.
Montesinos J, Pera M, Larrea D, Guardia-Laguarta C, Agrawal RR, Velasco KR, Yun TD, Stavrovskaya IG, Xu Y, Koo SY, Snead AM, Sproul AA, Area-Gomez E. The Alzheimer's disease-associated C99 fragment of APP regulates cellular cholesterol trafficking. EMBO J. 2020 Oct 15;39(20):e103791. Epub 2020 Aug 31 PubMed.
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