PMID- 29092095
OWN - NLM
STAT- MEDLINE
DCOM- 20180720
LR  - 20211204
IS  - 1755-5949 (Electronic)
IS  - 1755-5930 (Print)
IS  - 1755-5930 (Linking)
VI  - 24
IP  - 1
DP  - 2018 Jan
TI  - Abeta exacerbates alpha-synuclein-induced neurotoxicity through impaired insulin 
      signaling in alpha-synuclein-overexpressed human SK-N-MC neuronal cells.
PG  - 47-57
LID - 10.1111/cns.12772 [doi]
AB  - AIM: alpha-Synuclein (alphaSyn) is known as a small soluble protein abundantly expressed 
      in neuronal cells. Although its physiological role is still unclear, the 
      aggregation of alphaSyn has been recognized as responsible for some neurodegenerative 
      disorders such as dementia with Lewy bodies (DLB). In most cases, intracellular 
      abnormal aggregates are caused by protein-coding mutations that alter primary 
      structure and therefore increase propensity toward aggregation. However, no 
      pathogenic alterations or polymorphisms in alphaSyn are found in DLB patients so far, 
      suggesting genetic mutations may not play a major role in DLB pathogenesis. In 
      contrast, emerging evidence reveals that amyloid beta (Abeta) may contribute to 
      aggregate formation and exacerbate neurotoxicity of alphaSyn. However, the underlying 
      mechanism of action has remained unclear. METHODS: To investigate molecular 
      pathways involved in Abeta-mediated alphaSyn pathology, we established an in vitro model 
      for inducible alphaSyn overexpression in SK-N-MC human neuronal cells. RESULTS: Our 
      results demonstrated that Abeta treatment in alphaSyn-overexpressed neuronal cells 
      significantly increases alphaSyn intracellular aggregation and cytotoxicity. 
      Moreover, Abeta also caused AMP-activated protein kinase (AMPK) inhibition and 
      impaired insulin sensitivity, which leads to significant downregulation of 
      nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1) 
      antioxidant signaling to elicit alphaSyn aggregation. CONCLUSIONS: This raised the 
      possibility that insulin resistance could be one of the causative factors of alphaSyn 
      toxicity, and the strategies for insulin sensitization may have therapeutic 
      potential for synucleinopathies including DLB.
CI  - (c) 2017 John Wiley & Sons Ltd.
FAU - Chang, Ching-Chi
AU  - Chang CC
AD  - Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
AD  - Department of Psychiatry, Chung Shan Medical University Hospital, Taichung, 
      Taiwan.
FAU - Li, Hsin-Hua
AU  - Li HH
AD  - Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
FAU - Chang, Yen-Ting
AU  - Chang YT
AD  - Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
FAU - Ho, Ying-Jui
AU  - Ho YJ
AD  - Department of Psychology, Chung Shan Medical University, Taichung, Taiwan.
FAU - Hsieh, Ling-Jia
AU  - Hsieh LJ
AD  - Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
FAU - Chiu, Pai-Yi
AU  - Chiu PY
AD  - Department of Neurology, Show Chwan Memorial Hospital, Changhua, Taiwan.
FAU - Cheng, Yu-Shih
AU  - Cheng YS
AD  - Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
FAU - Lin, Chih-Li
AU  - Lin CL
AD  - Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
AD  - Department of Medical Research, Chung Shan Medical University Hospital, Taichung, 
      Taiwan.
FAU - Lai, Te-Jen
AU  - Lai TJ
AUID- ORCID: 0000-0003-4302-6182
AD  - Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
AD  - Department of Psychiatry, Chung Shan Medical University Hospital, Taichung, 
      Taiwan.
LA  - eng
PT  - Journal Article
DEP - 20171101
PL  - England
TA  - CNS Neurosci Ther
JT  - CNS neuroscience & therapeutics
JID - 101473265
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Hormone Antagonists)
RN  - 0 (Insulin)
RN  - 0 (Peptide Fragments)
RN  - 0 (alpha-Synuclein)
RN  - 0 (amyloid beta-protein (1-42))
RN  - 320T6RNW1F (Mifepristone)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinase Kinases
MH  - Amyloid beta-Peptides/*toxicity
MH  - Cell Line, Transformed
MH  - Gene Expression Regulation/drug effects/genetics
MH  - Hormone Antagonists/pharmacology
MH  - Humans
MH  - Insulin/*metabolism/pharmacology
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Mifepristone/pharmacology
MH  - Mutation/genetics
MH  - Neurons/*drug effects
MH  - Oxidative Stress/drug effects
MH  - Peptide Fragments/*toxicity
MH  - Protein Kinases/metabolism
MH  - Signal Transduction/*drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Time Factors
MH  - Transfection
MH  - alpha-Synuclein/*genetics/*metabolism
PMC - PMC6489723
OTO - NOTNLM
OT  - AMP-activated protein kinase
OT  - amyloid beta
OT  - dementia with Lewy bodies
OT  - insulin resistance
OT  - alpha-synuclein
COIS- The authors declare no conflict of interest.
EDAT- 2017/11/02 06:00
MHDA- 2018/07/22 06:00
PMCR- 2017/11/01
CRDT- 2017/11/02 06:00
PHST- 2017/06/20 00:00 [received]
PHST- 2017/10/10 00:00 [revised]
PHST- 2017/10/11 00:00 [accepted]
PHST- 2017/11/02 06:00 [pubmed]
PHST- 2018/07/22 06:00 [medline]
PHST- 2017/11/02 06:00 [entrez]
PHST- 2017/11/01 00:00 [pmc-release]
AID - CNS12772 [pii]
AID - 10.1111/cns.12772 [doi]
PST - ppublish
SO  - CNS Neurosci Ther. 2018 Jan;24(1):47-57. doi: 10.1111/cns.12772. Epub 2017 Nov 1.