PMID- 37147110
OWN - NLM
STAT- MEDLINE
DCOM- 20230706
LR  - 20230706
IS  - 1521-0111 (Electronic)
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 104
IP  - 1
DP  - 2023 Jul
TI  - Multiomics Analyses Identify Proline Endopeptidase-Like Protein As a Key 
      Regulator of Protein Trafficking, a Pathway Underlying Alzheimer's Disease 
      Pathogenesis.
PG  - 1-16
LID - 10.1124/molpharm.122.000641 [doi]
AB  - Current treatments for Alzheimer's disease (AD) help reduce symptoms for a 
      limited time but do not treat the underlying pathology. To identify potential 
      therapeutic targets for AD, an integrative network analysis was previously 
      carried out using 364 human postmortem control, mild cognitive impairment, and AD 
      brains. This analysis identified proline endopeptidase-like protein (PREPL), an 
      understudied protein, as a downregulated protein in late-onset AD patients. In 
      this study we investigate the role of PREPL. Analyses of data from human 
      postmortem samples and PREPL knockdown (KD) cells suggest that PREPL expression 
      modulates pathways associated with protein trafficking, synaptic activities, and 
      lipid metabolism. Furthermore, PREPL KD impairs cell proliferation and modulates 
      the structure of vesicles, levels of neuropeptide-processing enzymes, and 
      secretion of neuropeptides. In addition, decrease in PREPL levels leads to 
      changes in the levels of a number of synaptic proteins as well as changes in the 
      levels of secreted amyloid beta (Abeta) 42 peptide and Tau phosphorylation. Finally, 
      we report that local decrease in PREPL levels in mouse hippocampus attenuates 
      long-term potentiation, suggesting a role in synaptic plasticity. Together, our 
      results indicate that PREPL affects neuronal function by modulating protein 
      trafficking and synaptic function, an important mechanism of AD pathogenesis. 
      SIGNIFICANCE STATEMENT: Integrative network analysis reveals proline 
      endopeptidase-like protein (PREPL) to be downregulated in human sporadic 
      late-onset Alzheimer's disease brains. Down regulation of PREPL leads to 
      increases in amyloid beta secretion, Tau phosphorylation, and decreases in 
      protein trafficking and long-term potentiation.
CI  - U.S. Government work not protected by U.S. copyright.
FAU - Duarte, Mariana Lemos
AU  - Duarte ML
AUID- ORCID: 0000-0002-1611-7102
AD  - Department of Pharmacological Sciences (M.L.D., I.G., C.L., A.S., A.K.F., A.G., 
      S.M.M., L.A.D.), Department of Genetics and Genomics (M.W., B.Z.), and Department 
      of Neurology (M.L.D.), Icahn School of Medicine at Mount Sinai, New York, New 
      York.
FAU - Wang, Minghui
AU  - Wang M
AD  - Department of Pharmacological Sciences (M.L.D., I.G., C.L., A.S., A.K.F., A.G., 
      S.M.M., L.A.D.), Department of Genetics and Genomics (M.W., B.Z.), and Department 
      of Neurology (M.L.D.), Icahn School of Medicine at Mount Sinai, New York, New 
      York.
FAU - Gomes, Ivone
AU  - Gomes I
AD  - Department of Pharmacological Sciences (M.L.D., I.G., C.L., A.S., A.K.F., A.G., 
      S.M.M., L.A.D.), Department of Genetics and Genomics (M.W., B.Z.), and Department 
      of Neurology (M.L.D.), Icahn School of Medicine at Mount Sinai, New York, New 
      York.
FAU - Liu, Chenge
AU  - Liu C
AD  - Department of Pharmacological Sciences (M.L.D., I.G., C.L., A.S., A.K.F., A.G., 
      S.M.M., L.A.D.), Department of Genetics and Genomics (M.W., B.Z.), and Department 
      of Neurology (M.L.D.), Icahn School of Medicine at Mount Sinai, New York, New 
      York.
FAU - Sharma, Ali
AU  - Sharma A
AUID- ORCID: 0000-0001-6539-9970
AD  - Department of Pharmacological Sciences (M.L.D., I.G., C.L., A.S., A.K.F., A.G., 
      S.M.M., L.A.D.), Department of Genetics and Genomics (M.W., B.Z.), and Department 
      of Neurology (M.L.D.), Icahn School of Medicine at Mount Sinai, New York, New 
      York.
FAU - Fakira, Amanda K
AU  - Fakira AK
AD  - Department of Pharmacological Sciences (M.L.D., I.G., C.L., A.S., A.K.F., A.G., 
      S.M.M., L.A.D.), Department of Genetics and Genomics (M.W., B.Z.), and Department 
      of Neurology (M.L.D.), Icahn School of Medicine at Mount Sinai, New York, New 
      York.
FAU - Gupta, Achla
AU  - Gupta A
AD  - Department of Pharmacological Sciences (M.L.D., I.G., C.L., A.S., A.K.F., A.G., 
      S.M.M., L.A.D.), Department of Genetics and Genomics (M.W., B.Z.), and Department 
      of Neurology (M.L.D.), Icahn School of Medicine at Mount Sinai, New York, New 
      York.
FAU - Mack, Seshat M
AU  - Mack SM
AD  - Department of Pharmacological Sciences (M.L.D., I.G., C.L., A.S., A.K.F., A.G., 
      S.M.M., L.A.D.), Department of Genetics and Genomics (M.W., B.Z.), and Department 
      of Neurology (M.L.D.), Icahn School of Medicine at Mount Sinai, New York, New 
      York.
FAU - Zhang, Bin
AU  - Zhang B
AD  - Department of Pharmacological Sciences (M.L.D., I.G., C.L., A.S., A.K.F., A.G., 
      S.M.M., L.A.D.), Department of Genetics and Genomics (M.W., B.Z.), and Department 
      of Neurology (M.L.D.), Icahn School of Medicine at Mount Sinai, New York, New 
      York Bin.Zhang@mssm.edu Lakshmi.devi@mssm.edu.
FAU - Devi, Lakshmi A
AU  - Devi LA
AUID- ORCID: 0000-0002-2179-2874
AD  - Department of Pharmacological Sciences (M.L.D., I.G., C.L., A.S., A.K.F., A.G., 
      S.M.M., L.A.D.), Department of Genetics and Genomics (M.W., B.Z.), and Department 
      of Neurology (M.L.D.), Icahn School of Medicine at Mount Sinai, New York, New 
      York Bin.Zhang@mssm.edu Lakshmi.devi@mssm.edu.
LA  - eng
GR  - R37 DA008863/DA/NIDA NIH HHS/United States
GR  - U01 AG046170/AG/NIA NIH HHS/United States
GR  - R01 NS026880/NS/NINDS NIH HHS/United States
GR  - R01 DA008863/DA/NIDA NIH HHS/United States
GR  - R56 DA008863/DA/NIDA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20230505
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Amyloid beta-Peptides)
RN  - EC 3.4.21.26 (Prolyl Oligopeptidases)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - *Alzheimer Disease/genetics/metabolism
MH  - Amyloid beta-Peptides/metabolism
MH  - Disease Models, Animal
MH  - Mice, Transgenic
MH  - Multiomics
MH  - *Prolyl Oligopeptidases/metabolism
MH  - Protein Transport
PMC - PMC10289242
COIS- The authors do not have any conflicts of interest to disclose.
EDAT- 2023/05/06 09:42
MHDA- 2023/06/16 06:42
PMCR- 2023/07/01
CRDT- 2023/05/05 21:13
PHST- 2022/10/24 00:00 [received]
PHST- 2023/04/12 00:00 [accepted]
PHST- 2023/06/16 06:42 [medline]
PHST- 2023/05/06 09:42 [pubmed]
PHST- 2023/05/05 21:13 [entrez]
PHST- 2023/07/01 00:00 [pmc-release]
AID - molpharm.122.000641 [pii]
AID - MOL_AR2022000641 [pii]
AID - 10.1124/molpharm.122.000641 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2023 Jul;104(1):1-16. doi: 10.1124/molpharm.122.000641. Epub 2023 
      May 5.