Presenilin: A Multi-Functional Molecule in the Pathogenesis of Alzheimer's Disease and Other Neurodegenerative Diseases.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Alzheimer Disease*/metabolism ; Neurodegenerative Diseases*/etiology; Humans ; Amyloid beta-Peptides/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Presenilin-1/genetics ; Presenilin-1/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Apolipoproteins E ; Presenilin-2/genetics ; Presenilin-2/metabolism

Presenilin, a transmembrane protein primarily known for its role in Alzheimer's disease (AD) as part of the γ-secretase complex, has garnered increased attention due to its multifaceted functions in various cellular processes. Recent investigations have unveiled a plethora of functions beyond its amyloidogenic role. This review aims to provide a comprehensive overview of presenilin's diverse roles in AD and other neurodegenerative disorders. It includes a summary of well-known substrates of presenilin, such as its involvement in amyloid precursor protein (APP) processing and Notch signaling, along with other functions. Additionally, it highlights newly discovered functions, such as trafficking function, regulation of ferritin expression, apolipoprotein E (ApoE) secretion, the interaction of ApoE and presenilin, and the Aβ42-to-Aβ40-converting activity of ACE. This updated perspective underscores the evolving landscape of presenilin research, emphasizing its broader impact beyond established pathways. The incorporation of these novel findings accentuates the dynamic nature of presenilin's involvement in cellular processes, further advancing our comprehension of its multifaceted roles in neurodegenerative disorders. By synthesizing evidence from a range of studies, this review sheds light on the intricate web of presenilin functions and their implications in health and disease.

Biomolecules. 2022 Jul 22;12(8):. (PMID: 35892326)
Science. 2008 Mar 21;319(5870):1668-72. (PMID: 18309045)
Neurobiol Aging. 2009 Nov;30(11):1825-33. (PMID: 18314228)
J Biol Chem. 2009 Mar 20;284(12):8083-92. (PMID: 19112176)
Int J Mol Sci. 2020 Oct 21;21(20):. (PMID: 33096634)
Int Rev Cell Mol Biol. 2015;314:239-57. (PMID: 25619719)
Nat Immunol. 2015 Mar;16(3):229-36. (PMID: 25689443)
Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. (PMID: 27930341)
Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2017 Jun 8;33(6):488-492. (PMID: 29931895)
J Neurosci. 2022 Feb 23;42(8):1574-1586. (PMID: 34987110)
Brain Commun. 2020 Jul 20;2(2):fcaa100. (PMID: 33005890)
Neurodegener Dis. 2004;1(4-5):184-91. (PMID: 16908988)
Neuroreport. 2002 May 7;13(6):917-21. (PMID: 11997713)
Alzheimers Dement. 2011 Nov;7(6):574-8. (PMID: 22055974)
Elife. 2018 Jul 10;7:. (PMID: 29989545)
Mol Neurodegener. 2006 Jun 12;1:4. (PMID: 16930451)
J Clin Invest. 2005 Jun;115(6):1449-57. (PMID: 15931380)
Cell Calcium. 2011 Sep;50(3):303-9. (PMID: 21663966)
Semin Cell Dev Biol. 2020 Sep;105:27-42. (PMID: 32616437)
Signal Transduct Target Ther. 2022 Mar 24;7(1):95. (PMID: 35332121)
Acta Neuropathol Commun. 2021 Sep 30;9(1):162. (PMID: 34593029)
Semin Cell Dev Biol. 2020 Sep;105:54-63. (PMID: 32331992)
J Neurosci. 2007 Aug 8;27(32):8628-35. (PMID: 17687040)
Mol Ther Nucleic Acids. 2022 Mar 28;28:450-461. (PMID: 35505961)
Neuron. 2004 Apr 8;42(1):23-36. (PMID: 15066262)
N Engl J Med. 2013 Jul 25;369(4):341-50. (PMID: 23883379)
Trans Am Neurol Assoc. 1974;99:240-3. (PMID: 4282536)
Neural Regen Res. 2023 Aug;18(8):1679-1683. (PMID: 36751779)
Neurology. 2007 May 1;68(18):1501-8. (PMID: 17470753)
Cell Rep. 2019 Jul 16;28(3):655-669.e5. (PMID: 31315045)
J Biol Chem. 2019 Jun 21;294(25):9760-9770. (PMID: 31072831)
Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):12731-12736. (PMID: 29078389)
Int J Mol Sci. 2021 Dec 09;22(24):. (PMID: 34948057)
Alzheimers Dement (N Y). 2019 Jan 10;5:13-19. (PMID: 31650002)
Exp Mol Med. 2017 Dec 1;49(12):e405. (PMID: 29611543)
Neuron. 1998 Nov;21(5):1213-21. (PMID: 9856475)
Lancet. 2004 Sep 25-Oct 1;364(9440):1167-9. (PMID: 15451224)
Front Aging Neurosci. 2023 Feb 17;15:1098034. (PMID: 36875692)
J Biol Chem. 2007 Oct 26;282(43):31504-16. (PMID: 17716970)
Brain. 2014 Jul;137(Pt 7):1958-70. (PMID: 24860142)
Int J Mol Sci. 2023 Aug 11;24(16):. (PMID: 37628879)
Cell Death Dis. 2018 Aug 29;9(9):879. (PMID: 30158533)
Am J Alzheimers Dis Other Demen. 2006 Aug-Sep;21(4):281-6. (PMID: 16948293)
Neurochem Res. 2012 Jan;37(1):15-22. (PMID: 21842270)
Br J Pharmacol. 2014 Apr;171(8):2191-205. (PMID: 24148000)
J Cell Biol. 2004 Sep 27;166(7):1041-54. (PMID: 15452145)
Fluids Barriers CNS. 2021 Jan 7;18(1):3. (PMID: 33413468)
Transl Neurodegener. 2022 Jan 28;11(1):4. (PMID: 35090576)
J Alzheimers Dis. 2011;25(1):3-28. (PMID: 21335653)
Ann Neurol. 2004 May;55(5):604-6. (PMID: 15122699)
Neuron. 2007 Sep 6;55(5):697-711. (PMID: 17785178)
Brain Res. 2017 May 1;1662:57-64. (PMID: 28189560)
Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12. (PMID: 17245412)
J Neurosci Res. 2003 Oct 15;74(2):184-91. (PMID: 14515347)
J Neurosci. 2006 May 10;26(19):5180-9. (PMID: 16687509)
Biochem Biophys Res Commun. 2019 Aug 13;516(1):264-269. (PMID: 31235249)
J Neurosci. 2000 Oct 1;20(19):7268-78. (PMID: 11007884)
Oxid Med Cell Longev. 2012;2012:428010. (PMID: 22685618)
Nature. 2014 Aug 14;512(7513):166-170. (PMID: 25043039)
J Neurosci. 1998 Jun 15;18(12):4439-50. (PMID: 9614221)
Biochemistry. 2008 Mar 18;47(11):3370-8. (PMID: 18293935)
J Biol Chem. 2002 Feb 22;277(8):6318-23. (PMID: 11741961)
Cell. 2009 Apr 17;137(2):216-33. (PMID: 19379690)
J Neurosci. 2011 Feb 23;31(8):2781-91. (PMID: 21414900)
Science. 2019 Feb 15;363(6428):. (PMID: 30630874)
Ageing Res Rev. 2009 Apr;8(2):71-82. (PMID: 19101658)
Cell Death Differ. 2011 Apr;18(4):571-80. (PMID: 21311563)
Neuromolecular Med. 2002;2(1):29-45. (PMID: 12230303)
EMBO J. 2012 May 16;31(10):2261-74. (PMID: 22505025)
Neuron. 2008 Jun 26;58(6):871-83. (PMID: 18579078)
J Neurosci Res. 2010 Apr;88(5):1137-45. (PMID: 19885829)
Eur J Neurosci. 2005 Sep;22(5):1081-9. (PMID: 16176349)
Int J Mol Sci. 2020 Oct 30;21(21):. (PMID: 33143374)
Int J Biochem Cell Biol. 2004 Dec;36(12):2551-62. (PMID: 15325592)
Neurosci Lett. 2019 Aug 24;708:134345. (PMID: 31229623)
PLoS Genet. 2014 Oct 09;10(10):e1004704. (PMID: 25299611)
Proc Natl Acad Sci U S A. 1997 May 13;94(10):5090-4. (PMID: 9144195)
J Neurochem. 2008 Dec;107(6):1471-81. (PMID: 19094054)
J Biol Chem. 2003 Sep 26;278(39):37213-22. (PMID: 12857757)
J Neurol. 2005 Sep;252(9):1033-6. (PMID: 16170650)
Neurobiol Aging. 2017 Jan;49:145-153. (PMID: 27810638)
N Engl J Med. 2012 Aug 30;367(9):795-804. (PMID: 22784036)
J Neurochem. 2023 Mar;164(6):858-874. (PMID: 36582176)
Nature. 2009 Jul 30;460(7255):632-6. (PMID: 19641596)
Parkinsonism Relat Disord. 2020 Aug;77:21-25. (PMID: 32590294)
J Neurochem. 2007 Aug;102(3):848-57. (PMID: 17437536)
J Neurochem. 2005 Feb;92(3):628-36. (PMID: 15659232)
J Biol Chem. 2011 Sep 9;286(36):31153-8. (PMID: 21768095)
Neurol Ther. 2020 Dec;9(2):419-434. (PMID: 33089409)
J Neurosci. 2011 Feb 2;31(5):1688-92. (PMID: 21289177)
Semin Cell Dev Biol. 2020 Sep;105:12-26. (PMID: 32146031)
J Exp Med. 2017 Nov 6;214(11):3151-3169. (PMID: 29061693)
J Biol Chem. 2002 Nov 22;277(47):44754-9. (PMID: 12223485)
Neurobiol Aging. 2013 Feb;34(2):499-510. (PMID: 22475621)
Semin Cell Dev Biol. 2020 Sep;105:86-101. (PMID: 32423851)
Front Mol Neurosci. 2021 Aug 30;14:721047. (PMID: 34526879)
Oxid Med Cell Longev. 2019 Jul 28;2019:7284967. (PMID: 31467635)
Front Aging Neurosci. 2022 Jun 16;14:902525. (PMID: 35783133)
Int J Mol Sci. 2023 May 08;24(9):. (PMID: 37176125)
Curr Alzheimer Res. 2004 Feb;1(1):1-10. (PMID: 15975080)
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21435-40. (PMID: 21115843)
EMBO J. 2010 Oct 6;29(19):3408-20. (PMID: 20818335)
Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2777-82. (PMID: 21285369)
Autophagy. 2017;13(11):2004-2005. (PMID: 28914586)
Clin Anat. 2022 Jan;35(1):65-78. (PMID: 34558138)
Biochem Soc Trans. 2005 Aug;33(Pt 4):559-62. (PMID: 16042544)
Neurobiol Aging. 2016 Jan;37:208.e11-208.e17. (PMID: 26522186)
Nature. 1999 Apr 8;398(6727):513-7. (PMID: 10206644)
Cells. 2022 Jun 28;11(13):. (PMID: 35805131)
Cell. 2010 Jun 25;141(7):1146-58. (PMID: 20541250)
Curr Top Dev Biol. 2010;92:201-30. (PMID: 20816396)
J Neurochem. 2006 Mar;96(5):1322-35. (PMID: 16478525)
J Neurosci. 2013 Aug 14;33(33):13505-17. (PMID: 23946409)
Cold Spring Harb Perspect Med. 2012 Jan;2(1):a006304. (PMID: 22315713)
Exp Mol Med. 2022 Apr;54(4):433-446. (PMID: 35396575)
Nature. 2003 Mar 27;422(6930):438-41. (PMID: 12660785)
Am J Pathol. 2013 Jun;182(6):2322-31. (PMID: 23562443)

C19K07846 The Grant-in-Aid for Scientific Research; 22K07352 The Ministry of Education, Culture, Sports, Science, and Technology, Japan.; JP20dk0207050h0001 and JP20de010702 AMED; no The 24th General Assembly of the Japanese Association of Medical Sciences; no Daiko Foundation; no Hirose International Scholarship Foundation; no Hori Sciences and Arts Foundation; no Daiwa Securities Foundation; no Hirose Foundation

Keywords: ALS; Alzheimer’s disease; ApoE; Aβ42-to-Aβ40-converting activity of ACE; FTD; HD; PD; neurodegenerative diseases; presenilin; trafficking

0 (Amyloid beta-Peptides)
EC 3.4.- (Amyloid Precursor Protein Secretases)
0 (Presenilin-1)
0 (Amyloid beta-Protein Precursor)
0 (Apolipoproteins E)
0 (Presenilin-2)

Date Created: 20240210 Date Completed: 20240214 Latest Revision: 20240214

20240214

PMC10855926

10.3390/ijms25031757

38339035