. 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.

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Comments

  1. This very significant paper refutes one of the most “beautiful” sets of data supporting the amyloid hypothesis—the correlation between Aβ40:42 ratio and the mean age at onset of AD for FAD mutations in PSEN1. Figure 5 is particularly worthy of note both for its display of this lack of correlation and (my interpretation) as an example of statisticians’ sense of humor!

    Notably, both this paper and the commentary on it in PNAS by Kelleher and Shen continue to focus on Aβ production and γ-secretase activity as being important for development of AD. Kelleher and Shen in particular focus on the fact that 90 percent of FAD mutations in PSEN1 lead to reduction in Aβ40 and Aβ42 production to state that, “The study by Sun et al … point[s] to loss of γ-secretase activity as the primary molecular defect imposed by pathogenic PSEN1 mutations. Thus, therapeutic strategies aimed at restoring γ-secretase activity offer a valid and complementary approach to develop disease-modifying treatments for FAD.” But do they? Their comment ignores the 10 percent of FAD mutations in PSEN1 that did not lead to reduction in Aβ40 and Aβ42 production and, despite their having originally proposed the “presenilin hypothesis” (Shen and Kelleher, 2007), they (and the Sun et al. paper) largely ignore the possibility that (as we argued in our 2016 review paper, Jayne et al., 2016) it is the presenilin proteins’ other non-γ-secretase-dependent functions that may underlie AD pathology. If decreased γ-secretase activity caused FAD and the Aβ40:42 ratio is unimportant for the disease then one would expect also to find FAD mutations in other components of the γ-secretase complex—but there are none.

    In our 2016 review we suggest that changes in the non-γ-secretase functions of the presenilin holoproteins may underlie FAD. In particular, the effects of FAD mutations on lysosomal acidification are a strong candidate for the underlying defect. Sun et al.’s paper and Kelleher and Shen’s commentary have been published almost simultaneously with Fazzari et al.’s publication in Nature showing that the PLD3 gene, for which decreased expression correlates with sporadic AD risk, appears to affect lysosome function rather than APP metabolism. It would be wonderful to see the comprehensive analysis performed by Sun et al. expanded to examine the non-γ-secretase functions of PSEN1.

    References:

    . 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.

    . The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):403-9. PubMed.

    . 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.

    . PLD3 gene and processing of APP. Nature. 2017 Jan 25;541(7638):E1-E2. PubMed.

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Mutations

  1. PSEN1 R35Q
  2. PSEN1 A79V
  3. PSEN1 V82L
  4. PSEN1 L85P
  5. PSEN1 V89L (G>T)
  6. PSEN1 C92S
  7. PSEN1 V96F
  8. PSEN1 V94M
  9. PSEN1 V97L
  10. PSEN1 F105I
  11. PSEN1 L113Q
  12. PSEN1 Y115H
  13. PSEN1 Y115C
  14. PSEN1 T116N
  15. PSEN1 P117A
  16. PSEN1 E120D (A>C)
  17. PSEN1 E123K
  18. PSEN1 A136G
  19. PSEN1 M139V
  20. PSEN1 I143V
  21. PSEN1 I143T
  22. PSEN1 M146L (A>C)
  23. PSEN1 M146L (A>T)
  24. PSEN1 T147I
  25. PSEN1 L153V
  26. PSEN1 Y154N
  27. PSEN1 H163Y
  28. PSEN1 H163R
  29. PSEN1 W165G
  30. PSEN1 L166del
  31. PSEN1 S169P
  32. PSEN1 S170F
  33. PSEN1 L173W
  34. PSEN1 L174M
  35. PSEN1 F177L
  36. PSEN1 E184D
  37. PSEN1 G206S
  38. PSEN1 G206A
  39. PSEN1 G209R
  40. PSEN1 G209V
  41. PSEN1 H214D
  42. PSEN1 L219F
  43. PSEN1 Q223R
  44. PSEN1 I229F
  45. PSEN1 A231T
  46. PSEN1 M233L (A>C)
  47. PSEN1 M233L (A>T)
  48. PSEN1 M233T
  49. PSEN1 F237I
  50. PSEN1 K239N
  51. PSEN1 T245P
  52. PSEN1 A246E
  53. PSEN1 L248R
  54. PSEN1 L250S
  55. PSEN1 Y256S
  56. PSEN1 A260V
  57. PSEN1 V261F
  58. PSEN1 C263R
  59. PSEN1 P264L
  60. PSEN1 G266S
  61. PSEN1 P267S
  62. PSEN1 R269G
  63. PSEN1 L271V
  64. PSEN1 V272A
  65. PSEN1 E273A
  66. PSEN1 T274R
  67. PSEN1 R278K
  68. PSEN1 E280A (Paisa)
  69. PSEN1 E280G
  70. PSEN1 P284S
  71. PSEN1 A285V
  72. PSEN1 E318G
  73. PSEN1 R358Q
  74. PSEN1 S365A
  75. PSEN1 D333G
  76. PSEN1 G378E
  77. PSEN1 G378V
  78. PSEN1 G384A
  79. PSEN1 F386S
  80. PSEN1 S390I
  81. PSEN1 V391F
  82. PSEN1 G394V
  83. PSEN1 N405S
  84. PSEN1 A409T
  85. PSEN1 C410Y
  86. PSEN1 V412I
  87. PSEN1 L381V
  88. PSEN1 L418F
  89. PSEN1 L424V
  90. PSEN1 A426P
  91. PSEN1 A431E (Jalisco)
  92. PSEN1 A434C
  93. PSEN1 L435F
  94. PSEN1 P436S
  95. PSEN1 S290C;T291_S319del (ΔE9)
  96. PSEN1 S290C;T291_S319del (ΔE9Finn)
  97. PSEN1 869-22_869-23ins18 (ΔE9)
  98. PSEN1 S290C;T291_S319del G>A (ΔE9)
  99. PSEN1 S290C;T291_S319del G>T (ΔE9)
  100. PSEN1 I83_M84del (DelIM)
  101. PSEN1 S169del (ΔS169)
  102. PSEN1 T354I
  103. PSEN1 L286V
  104. PSEN1 L166P
  105. PSEN1 D40del (delGAC)
  106. PSEN1 E120D (A>T)
  107. PSEN1 F176L
  108. PSEN1 L226F
  109. PSEN1 I202F
  110. PSEN1 R377W
  111. PSEN1 A396T
  112. PSEN1 R108Q
  113. PSEN1 R352C
  114. PSEN1 T99A
  115. PSEN1 S290C;T291_S319del A>G (ΔE9)
  116. PSEN1 D40del (delACG)
  117. PSEN1 V89L (G>C)
  118. PSEN1 I213L