PMID- 28495961
OWN - NLM
STAT- MEDLINE
DCOM- 20171019
LR  - 20220512
IS  - 1943-2631 (Electronic)
IS  - 0016-6731 (Print)
IS  - 0016-6731 (Linking)
VI  - 206
IP  - 3
DP  - 2017 Jul
TI  - An Evolutionarily Conserved Role of Presenilin in Neuronal Protection in the 
      Aging Drosophila Brain.
PG  - 1479-1493
LID - 10.1534/genetics.116.196881 [doi]
AB  - Mutations in the Presenilin genes are the major genetic cause of Alzheimer's 
      disease. Presenilin and Nicastrin are essential components of gamma-secretase, a 
      multi-subunit protease that cleaves Type I transmembrane proteins. Genetic 
      studies in mice previously demonstrated that conditional inactivation of 
      Presenilin or Nicastrin in excitatory neurons of the postnatal forebrain results 
      in memory deficits, synaptic impairment, and age-dependent neurodegeneration. The 
      roles of Drosophila Presenilin (Psn) and Nicastrin (Nct) in the adult fly brain, 
      however, are unknown. To knockdown (KD) Psn or Nct selectively in neurons of the 
      adult brain, we generated multiple shRNA lines. Using a ubiquitous driver, these 
      shRNA lines resulted in 80-90% reduction of mRNA and pupal lethality-a phenotype 
      that is shared with Psn and Nct mutants carrying nonsense mutations. Furthermore, 
      expression of these shRNAs in the wing disc caused notching wing phenotypes, 
      which are also shared with Psn and Nct mutants. Similar to Nct, neuron-specific 
      Psn KD using two independent shRNA lines led to early mortality and rough eye 
      phenotypes, which were rescued by a fly Psn transgene. Interestingly, conditional 
      KD (cKD) of Psn or Nct in adult neurons using the elav-Gal4 and tubulin-Gal80(ts) 
      system caused shortened lifespan, climbing defects, increases in apoptosis, and 
      age-dependent neurodegeneration. Together, these findings demonstrate that, 
      similar to their mammalian counterparts, Drosophila Psn and Nct are required for 
      neuronal survival during aging and normal lifespan, highlighting an 
      evolutionarily conserved role of Presenilin in neuronal protection in the aging 
      brain.
CI  - Copyright (c) 2017 by the Genetics Society of America.
FAU - Kang, Jongkyun
AU  - Kang J
AD  - Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, Massachusetts 02115.
FAU - Shin, Sarah
AU  - Shin S
AD  - Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, Massachusetts 02115.
FAU - Perrimon, Norbert
AU  - Perrimon N
AD  - Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115 
      perrimon@receptor.med.harvard.edu jshen@bwh.harvard.edu.
AD  - Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 
      02115.
FAU - Shen, Jie
AU  - Shen J
AD  - Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, Massachusetts 02115 perrimon@receptor.med.harvard.edu 
      jshen@bwh.harvard.edu.
AD  - Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115.
LA  - eng
GR  - R01 NS041783/NS/NINDS NIH HHS/United States
GR  - R01 NS042818/NS/NINDS NIH HHS/United States
GR  - R01 NS101745/NS/NINDS NIH HHS/United States
GR  - RF1 NS041783/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170511
PL  - United States
TA  - Genetics
JT  - Genetics
JID - 0374636
RN  - 0 (Codon, Nonsense)
RN  - 0 (Drosophila Proteins)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Presenilins)
RN  - 0 (Psn protein, Drosophila)
RN  - 0 (nicastrin protein)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
SB  - IM
MH  - Aging/*genetics
MH  - Amyloid Precursor Protein Secretases/genetics/metabolism
MH  - Animals
MH  - Apoptosis
MH  - Brain/cytology/growth & development/*metabolism
MH  - Codon, Nonsense
MH  - Drosophila/genetics/growth & development/metabolism
MH  - Drosophila Proteins/*genetics/metabolism
MH  - Evolution, Molecular
MH  - Membrane Glycoproteins/genetics/metabolism
MH  - Neurons/cytology/*metabolism
MH  - Presenilins/*genetics/metabolism
PMC - PMC5500145
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - brain
OT  - conditional knockdown
OT  - shRNA
OT  - gamma-secretase
EDAT- 2017/05/13 06:00
MHDA- 2017/10/20 06:00
PMCR- 2018/07/01
CRDT- 2017/05/13 06:00
PHST- 2016/10/17 00:00 [received]
PHST- 2017/05/05 00:00 [accepted]
PHST- 2017/05/13 06:00 [pubmed]
PHST- 2017/10/20 06:00 [medline]
PHST- 2017/05/13 06:00 [entrez]
PHST- 2018/07/01 00:00 [pmc-release]
AID - genetics.116.196881 [pii]
AID - 196881 [pii]
AID - 10.1534/genetics.116.196881 [doi]
PST - ppublish
SO  - Genetics. 2017 Jul;206(3):1479-1493. doi: 10.1534/genetics.116.196881. Epub 2017 
      May 11.