PMID- 37637959
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240313
IS  - 1663-4365 (Print)
IS  - 1663-4365 (Electronic)
IS  - 1663-4365 (Linking)
VI  - 15
DP  - 2023
TI  - Honokiol decreases alpha-synuclein mRNA levels and reveals novel targets for 
      modulating alpha-synuclein expression.
PG  - 1179086
LID - 10.3389/fnagi.2023.1179086 [doi]
LID - 1179086
AB  - BACKGROUND: Intracytoplasmic inclusions comprised of aggregated alpha-synuclein 
      (alphasyn) represent a key histopathological feature of neurological disorders 
      collectively termed "synucleinopathies," which includes Parkinson's disease (PD). 
      Mutations and multiplications in the SNCA gene encoding alphasyn cause familial forms 
      of PD and a large body of evidence indicate a correlation between alphasyn 
      accumulation and disease. Decreasing alphasyn expression is recognized as a valid 
      target for PD therapeutics, with down-regulation of SNCA expression potentially 
      attenuating downstream cascades of pathologic events. Here, we evaluated if 
      Honokiol (HKL), a polyphenolic compound derived from magnolia tree bark with 
      demonstrated neuroprotective properties, can modulate alphasyn levels in multiple 
      experimental models. METHODS: Human neuroglioma cells stably overexpressing alphasyn, 
      mouse primary neurons, and human iPSC-derived neurons were exposed to HKL and 
      alphasyn protein and SNCA messenger RNA levels were assessed. The effect of HKL on 
      rotenone-induced overexpression of alphasyn levels was further assessed and 
      transcriptional profiling of mouse cortical neurons treated with HKL was 
      performed to identify potential targets of HKL. RESULTS: We demonstrate that HKL 
      can successfully reduce alphasyn protein levels and SNCA expression in multiple in 
      vitro models of PD with our data supporting a mechanism whereby HKL acts by 
      post-transcriptional modulation of SNCA rather than modulating alphasyn protein 
      degradation. Transcriptional profiling of mouse cortical neurons treated with HKL 
      identifies several differentially expressed genes (DEG) as potential targets to 
      modulate SNCA expression. CONCLUSION: This study supports a HKL-mediated 
      downregulation of SNCA as a viable strategy to modify disease progression in PD 
      and other synucleinopathies. HKL has potential as a powerful tool for 
      investigating SNCA gene modulation and its downstream effects.
CI  - Copyright (c) 2023 Fagen, Burgess, Lim, Amerna, Kaya, Faroqi, Perisetla, DeMeo, 
      Stojkovska, Quiriconi, Mazzulli, Delenclos, Boschen and McLean.
FAU - Fagen, Sara J
AU  - Fagen SJ
AD  - Department of Neuroscience, Mayo Clinic, Jackson ville, FL, United States.
FAU - Burgess, Jeremy D
AU  - Burgess JD
AD  - Department of Neuroscience, Mayo Clinic, Jackson ville, FL, United States.
AD  - Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic College of 
      Medicine, Rochester, MN, United States.
FAU - Lim, Melina J
AU  - Lim MJ
AD  - Department of Neuroscience, Mayo Clinic, Jackson ville, FL, United States.
FAU - Amerna, Danilyn
AU  - Amerna D
AD  - Department of Neuroscience, Mayo Clinic, Jackson ville, FL, United States.
FAU - Kaya, Zeynep B
AU  - Kaya ZB
AD  - Department of Neuroscience, Mayo Clinic, Jackson ville, FL, United States.
FAU - Faroqi, Ayman H
AU  - Faroqi AH
AD  - Department of Neuroscience, Mayo Clinic, Jackson ville, FL, United States.
AD  - Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic College of 
      Medicine, Rochester, MN, United States.
FAU - Perisetla, Priyanka
AU  - Perisetla P
AD  - Department of Neuroscience, Mayo Clinic, Jackson ville, FL, United States.
FAU - DeMeo, Natasha N
AU  - DeMeo NN
AD  - Department of Neuroscience, Mayo Clinic, Jackson ville, FL, United States.
FAU - Stojkovska, Iva
AU  - Stojkovska I
AD  - Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
FAU - Quiriconi, Drew J
AU  - Quiriconi DJ
AD  - Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
FAU - Mazzulli, Joseph R
AU  - Mazzulli JR
AD  - Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
FAU - Delenclos, Marion
AU  - Delenclos M
AD  - Department of Neuroscience, Mayo Clinic, Jackson ville, FL, United States.
FAU - Boschen, Suelen L
AU  - Boschen SL
AD  - Department of Neuroscience, Mayo Clinic, Jackson ville, FL, United States.
AD  - Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic College of 
      Medicine, Rochester, MN, United States.
AD  - Department of Neurosurgery, Mayo Clinic, Jacksonville, FL, United States.
FAU - McLean, Pamela J
AU  - McLean PJ
AD  - Department of Neuroscience, Mayo Clinic, Jackson ville, FL, United States.
AD  - Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic College of 
      Medicine, Rochester, MN, United States.
LA  - eng
GR  - R01 NS092823/NS/NINDS NIH HHS/United States
PT  - Journal Article
DEP - 20230810
PL  - Switzerland
TA  - Front Aging Neurosci
JT  - Frontiers in aging neuroscience
JID - 101525824
PMC - PMC10449643
OTO - NOTNLM
OT  - Parkinson's disease
OT  - SNCA
OT  - alpha-synuclein (alphaSyn)
OT  - natural compound
OT  - polyphenol
OT  - therapeutic target
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/08/28 06:42
MHDA- 2023/08/28 06:43
PMCR- 2023/01/01
CRDT- 2023/08/28 04:56
PHST- 2023/03/10 00:00 [received]
PHST- 2023/07/17 00:00 [accepted]
PHST- 2023/08/28 06:43 [medline]
PHST- 2023/08/28 06:42 [pubmed]
PHST- 2023/08/28 04:56 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.3389/fnagi.2023.1179086 [doi]
PST - epublish
SO  - Front Aging Neurosci. 2023 Aug 10;15:1179086. doi: 10.3389/fnagi.2023.1179086. 
      eCollection 2023.