PMID- 37996068
OWN - NLM
STAT- MEDLINE
DCOM- 20240104
LR  - 20240106
IS  - 1943-2631 (Electronic)
IS  - 0016-6731 (Print)
IS  - 0016-6731 (Linking)
VI  - 226
IP  - 1
DP  - 2024 Jan 3
TI  - Lipophorin receptors genetically modulate neurodegeneration caused by reduction 
      of Psn expression in the aging Drosophila brain.
LID - 10.1093/genetics/iyad202 [doi]
LID - iyad202
AB  - Mutations in the Presenilin (PSEN) genes are the most common cause of early-onset 
      familial Alzheimer's disease (FAD). Studies in cell culture, in vitro biochemical 
      systems, and knockin mice showed that PSEN mutations are loss-of-function 
      mutations, impairing gamma-secretase activity. Mouse genetic analysis highlighted the 
      importance of Presenilin (PS) in learning and memory, synaptic plasticity and 
      neurotransmitter release, and neuronal survival, and Drosophila studies further 
      demonstrated an evolutionarily conserved role of PS in neuronal survival during 
      aging. However, molecular pathways that interact with PS in neuronal survival 
      remain unclear. To identify genetic modifiers that modulate PS-dependent neuronal 
      survival, we developed a new DrosophilaPsn model that exhibits age-dependent 
      neurodegeneration and increases of apoptosis. Following a bioinformatic analysis, 
      we tested top ranked candidate genes by selective knockdown (KD) of each gene in 
      neurons using two independent RNAi lines in Psn KD models. Interestingly, 4 of 
      the 9 genes enhancing neurodegeneration in Psn KD flies are involved in lipid 
      transport and metabolism. Specifically, neuron-specific KD of lipophorin 
      receptors, lpr1 and lpr2, dramatically worsens neurodegeneration in Psn KD flies, 
      and overexpression of lpr1 or lpr2 does not alleviate Psn KD-induced 
      neurodegeneration. Furthermore, lpr1 or lpr2 KD alone also leads to 
      neurodegeneration, increased apoptosis, climbing defects, and shortened lifespan. 
      Lastly, heterozygotic deletions of lpr1 and lpr2 or homozygotic deletions of lpr1 
      or lpr2 similarly lead to age-dependent neurodegeneration and further exacerbate 
      neurodegeneration in Psn KD flies. These findings show that LpRs modulate 
      Psn-dependent neuronal survival and are critically important for neuronal 
      integrity in the aging brain.
CI  - (c) The Author(s) 2023. Published by Oxford University Press on behalf of The 
      Genetics Society of America. All rights reserved. For permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Kang, Jongkyun
AU  - Kang J
AD  - Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, MA 02115, USA.
FAU - Zhang, Chen
AU  - Zhang C
AUID- ORCID: 0000-0001-9494-1378
AD  - Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, MA 02115, USA.
FAU - Wang, Yuhao
AU  - Wang Y
AD  - Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute 
      of Technology, Cambridge, MA 02139, USA.
FAU - Peng, Jian
AU  - Peng J
AD  - Department of Computer Science, University of Illinois at Urbana-Champaign, 
      Champaign, IL 61801, USA.
FAU - Berger, Bonnie
AU  - Berger B
AD  - Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute 
      of Technology, Cambridge, MA 02139, USA.
AD  - Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA 
      02139, USA.
FAU - Perrimon, Norbert
AU  - Perrimon N
AD  - Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
AD  - Howard Hughes Medical Institute, Boston, MA 02115, USA.
FAU - Shen, Jie
AU  - Shen J
AUID- ORCID: 0000-0003-1160-7118
AD  - Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, MA 02115, USA.
AD  - Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
LA  - eng
GR  - P40 OD018537/OD/NIH HHS/United States
GR  - R01 NS101745/NS/NINDS NIH HHS/United States
GR  - R01NS101745/GF/NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Genetics
JT  - Genetics
JID - 0374636
RN  - 0 (lipophorin receptor)
RN  - 0 (Presenilins)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Drosophila/genetics/metabolism
MH  - Presenilins/genetics/metabolism
MH  - Brain/metabolism
MH  - *Alzheimer Disease/genetics
MH  - Aging/genetics
PMC - PMC10763532
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - Presenilin
OT  - genetic modifier
OT  - lipid transport and metabolism
OT  - lipoproteins
COIS- Conflicts of interest J.S. has financial interests in iNeuro Therapeutics. J.S.'s 
      interests are managed by Mass General Brigham in accordance with the 
      institutional conflict of interest policies.
EDAT- 2023/11/24 00:42
MHDA- 2024/01/04 11:45
PMCR- 2024/11/23
CRDT- 2023/11/23 19:33
PHST- 2023/10/11 00:00 [received]
PHST- 2023/11/12 00:00 [accepted]
PHST- 2024/11/23 00:00 [pmc-release]
PHST- 2024/01/04 11:45 [medline]
PHST- 2023/11/24 00:42 [pubmed]
PHST- 2023/11/23 19:33 [entrez]
AID - 7444947 [pii]
AID - iyad202 [pii]
AID - 10.1093/genetics/iyad202 [doi]
PST - ppublish
SO  - Genetics. 2024 Jan 3;226(1):iyad202. doi: 10.1093/genetics/iyad202.