PMID- 31727601
OWN - NLM
STAT- MEDLINE
DCOM- 20200430
LR  - 20210110
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 50
DP  - 2019 Dec
TI  - Small molecule modulator of aggrephagy regulates neuroinflammation to curb 
      pathogenesis of neurodegeneration.
PG  - 260-273
LID - S2352-3964(19)30706-6 [pii]
LID - 10.1016/j.ebiom.2019.10.036 [doi]
AB  - BACKGROUND: Plethora of efforts fails to yield a single drug to reverse the 
      pathogenesis of Parkinson's disease (PD) and related alpha-synucleopathies. METHODS: 
      Using chemical biology, we identified a small molecule inhibitor of c-abl kinase, 
      PD180970 that could potentially clear the toxic protein aggregates. Genetic, 
      molecular, cell biological and immunological assays were performed to understand 
      the mechanism of action. In vivo preclinical disease model of PD was used to 
      assess its neuroprotection efficacy. FINDINGS: In this report, we show the 
      ability of a small molecule inhibitor of tyrosine kinases, PD180970, to induce 
      autophagy (cell lines and mice midbrain) in an mTOR-independent manner and 
      ameliorate the alpha-synuclein mediated toxicity. PD180970 also exerts 
      anti-neuroinflammatory potential by inhibiting the release of proinflammatory 
      cytokines such as IL-6 (interleukin-6) and MCP-1 (monocyte chemoattractant 
      protein-1) through reduction of TLR-4 (toll like receptor-4) mediated NF-kappaB 
      (nuclear factor kappa-light-chain-enhancer of activated B cells) activation. In 
      vivo studies show that PD180970 is neuroprotective by degrading the toxic protein 
      oligomers through induction of autophagy and subsiding the microglial activation. 
      INTERPRETATION: These protective mechanisms ensure the negation of Parkinson's 
      disease related motor impairments. FUND: This work was supported by Wellcome 
      Trust/DBT India Alliance Intermediate Fellowship (500159-Z-09-Z), DST-SERB grant 
      (EMR/2015/001946), DBT (BT/INF/22/SP27679/2018) and JNCASR intramural funds to 
      RM, and SERB, DST (SR/SO/HS/0121/2012) to PAA, and DST-SERB (SB/YS/LS-215/2013) 
      to JPC and BIRAC funding to ETA C-CAMP.
CI  - Copyright (c) 2019 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Sn, Suresh
AU  - Sn S
AD  - Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced 
      Scientific Research, Jakkur, Bangalore, India; Centre for Brain Research (CBR), 
      IISc, Bangalore, India.
FAU - Pandurangi, Janhavi
AU  - Pandurangi J
AD  - Centre for Cellular and Molecular Platforms (C-CAMP), Bangalore Life Sciences 
      Cluster (BLiSC), Tata Institute of Fundamental Research, Bangalore, India.
FAU - Murumalla, Ravi
AU  - Murumalla R
AD  - Centre for Cellular and Molecular Platforms (C-CAMP), Bangalore Life Sciences 
      Cluster (BLiSC), Tata Institute of Fundamental Research, Bangalore, India.
FAU - Dj, Vidyadhara
AU  - Dj V
AD  - Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced 
      Scientific Research, Jakkur, Bangalore, India; Yale University, USA.
FAU - Garimella, Lakshmi
AU  - Garimella L
AD  - Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced 
      Scientific Research, Jakkur, Bangalore, India.
FAU - Acharya, Achyuth
AU  - Acharya A
AD  - Centre for Cellular and Molecular Platforms (C-CAMP), Bangalore Life Sciences 
      Cluster (BLiSC), Tata Institute of Fundamental Research, Bangalore, India.
FAU - Rai, Shashank
AU  - Rai S
AD  - Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced 
      Scientific Research, Jakkur, Bangalore, India; MRC Laboratory of Molecular 
      Biology, Cambridge, UK.
FAU - Paul, Abhik
AU  - Paul A
AD  - Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, 
      Jakkur, Bangalore, India.
FAU - Yarreiphang, Haorei
AU  - Yarreiphang H
AD  - Department of Neurophysiology, National Institute of Mental Health and Neuro 
      Sciences, Bangalore, India.
FAU - Pillai, Malini S
AU  - Pillai MS
AD  - Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced 
      Scientific Research, Jakkur, Bangalore, India.
FAU - Giridharan, Mridhula
AU  - Giridharan M
AD  - Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced 
      Scientific Research, Jakkur, Bangalore, India.
FAU - Clement, James P
AU  - Clement JP
AD  - Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, 
      Jakkur, Bangalore, India.
FAU - Alladi, Phalguni Anand
AU  - Alladi PA
AD  - Department of Neurophysiology, National Institute of Mental Health and Neuro 
      Sciences, Bangalore, India.
FAU - Saiyed, Taslimarif
AU  - Saiyed T
AD  - Centre for Cellular and Molecular Platforms (C-CAMP), Bangalore Life Sciences 
      Cluster (BLiSC), Tata Institute of Fundamental Research, Bangalore, India.
FAU - Manjithaya, Ravi
AU  - Manjithaya R
AD  - Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced 
      Scientific Research, Jakkur, Bangalore, India; Neuroscience Unit, Jawaharlal 
      Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, India. 
      Electronic address: ravim@jncasr.ac.in.
LA  - eng
PT  - Journal Article
DEP - 20191111
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
RN  - 0 (Biomarkers)
RN  - 0 (Cytokines)
RN  - 0 (Interleukin-6)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Protein Aggregates)
RN  - 0 (Pyridones)
RN  - 0 (Pyrimidines)
RN  - 0 (alpha-Synuclein)
RN  - TSO2IAD7WJ (PD 180970)
SB  - IM
MH  - Animals
MH  - Biomarkers
MH  - Cell Line
MH  - Cytokines/metabolism
MH  - Disease Models, Animal
MH  - Humans
MH  - Immunohistochemistry
MH  - Interleukin-6/metabolism
MH  - Lipopolysaccharides/metabolism
MH  - Macroautophagy
MH  - Male
MH  - Mice
MH  - Microglia/drug effects/metabolism
MH  - Neurodegenerative Diseases/drug therapy/*etiology/*metabolism/physiopathology
MH  - Neurons/metabolism
MH  - Neuroprotective Agents/*pharmacology/therapeutic use
MH  - Oxidative Stress
MH  - Protein Aggregates/drug effects
MH  - Protein Aggregation, Pathological/drug therapy/*metabolism
MH  - Pyridones/pharmacology/therapeutic use
MH  - Pyrimidines/pharmacology/therapeutic use
MH  - alpha-Synuclein/metabolism
PMC - PMC6921191
EDAT- 2019/11/16 06:00
MHDA- 2020/05/01 06:00
PMCR- 2019/11/11
CRDT- 2019/11/16 06:00
PHST- 2019/02/16 00:00 [received]
PHST- 2019/10/13 00:00 [revised]
PHST- 2019/10/20 00:00 [accepted]
PHST- 2019/11/16 06:00 [pubmed]
PHST- 2020/05/01 06:00 [medline]
PHST- 2019/11/16 06:00 [entrez]
PHST- 2019/11/11 00:00 [pmc-release]
AID - S2352-3964(19)30706-6 [pii]
AID - 10.1016/j.ebiom.2019.10.036 [doi]
PST - ppublish
SO  - EBioMedicine. 2019 Dec;50:260-273. doi: 10.1016/j.ebiom.2019.10.036. Epub 2019 
      Nov 11.