PMID- 24368770
OWN - NLM
STAT- MEDLINE
DCOM- 20140425
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 289
IP  - 9
DP  - 2014 Feb 28
TI  - Rheb GTPase regulates beta-secretase levels and amyloid beta generation.
PG  - 5799-808
LID - 10.1074/jbc.M113.532713 [doi]
AB  - The beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (beta-secretase, BACE1) 
      initiates amyloidogenic processing of APP to generate amyloid beta (Abeta), which is a 
      hallmark of Alzheimer disease (AD) pathology. Cerebral levels of BACE1 are 
      elevated in individuals with AD, but the molecular mechanisms are not completely 
      understood. We demonstrate that Rheb GTPase (Ras homolog enriched in brain), 
      which induces mammalian target of rapamycin (mTOR) activity, is a physiological 
      regulator of BACE1 stability and activity. Rheb overexpression depletes BACE1 
      protein levels and reduces Abeta generation, whereas the RNAi knockdown of 
      endogenous Rheb promotes BACE1 accumulation, and this effect by Rheb is 
      independent of its mTOR signaling. Moreover, GTP-bound Rheb interacts with BACE1 
      and degrades it through proteasomal and lysosomal pathways. Finally, we 
      demonstrate that Rheb levels are down-regulated in the AD brain, which is 
      consistent with an increased BACE1 expression. Altogether, our study defines Rheb 
      as a novel physiological regulator of BACE1 levels and Abeta generation, and the 
      Rheb-BACE1 circuitry may have a role in brain biology and disease.
FAU - Shahani, Neelam
AU  - Shahani N
AD  - From the Department of Neuroscience, The Scripps Research Institute, Florida, 
      Jupiter, Florida 33458.
FAU - Pryor, William
AU  - Pryor W
FAU - Swarnkar, Supriya
AU  - Swarnkar S
FAU - Kholodilov, Nikolai
AU  - Kholodilov N
FAU - Thinakaran, Gopal
AU  - Thinakaran G
FAU - Burke, Robert E
AU  - Burke RE
FAU - Subramaniam, Srinivasa
AU  - Subramaniam S
LA  - eng
GR  - R24 MH068855/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20131224
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (APP protein, human)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Neuropeptides)
RN  - 0 (RHEB protein, human)
RN  - 0 (Ras Homolog Enriched in Brain Protein)
RN  - 0 (Rheb protein, mouse)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.46 (BACE1 protein, human)
RN  - EC 3.4.23.46 (Bace1 protein, mouse)
RN  - EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
SB  - IM
MH  - Alzheimer Disease/genetics/metabolism/pathology
MH  - Amyloid Precursor Protein Secretases/*biosynthesis/genetics
MH  - Amyloid beta-Protein Precursor/genetics/*metabolism
MH  - Animals
MH  - Aspartic Acid Endopeptidases/*biosynthesis/genetics
MH  - Brain/*metabolism/pathology
MH  - Gene Expression Regulation, Enzymologic/genetics
MH  - HEK293 Cells
MH  - Humans
MH  - Mice
MH  - Monomeric GTP-Binding Proteins/genetics/*metabolism
MH  - Neuropeptides/genetics/*metabolism
MH  - Protein Binding
MH  - Proteolysis
MH  - Ras Homolog Enriched in Brain Protein
PMC - PMC3937651
OTO - NOTNLM
OT  - Aging
OT  - Amyloid
OT  - GTPase
OT  - Protein Stability
OT  - Secretases
EDAT- 2013/12/26 06:00
MHDA- 2014/04/26 06:00
PMCR- 2015/02/28
CRDT- 2013/12/26 06:00
PHST- 2013/12/26 06:00 [entrez]
PHST- 2013/12/26 06:00 [pubmed]
PHST- 2014/04/26 06:00 [medline]
PHST- 2015/02/28 00:00 [pmc-release]
AID - S0021-9258(20)44045-1 [pii]
AID - M113.532713 [pii]
AID - 10.1074/jbc.M113.532713 [doi]
PST - ppublish
SO  - J Biol Chem. 2014 Feb 28;289(9):5799-808. doi: 10.1074/jbc.M113.532713. Epub 2013 
      Dec 24.