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Small molecule modulator of aggrephagy regulates neuroinflammation to curb pathogenesis of neurodegeneration
- Source :
- EBioMedicine, Vol 50, Iss, Pp 260-273 (2019), EBioMedicine
- Publication Year :
- 2019
- Publisher :
- Elsevier, 2019.
-
Abstract
- BACKGROUND: Plethora of efforts fails to yield a single drug to reverse the pathogenesis of Parkinson's disease (PD) and related α-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 α-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-κB (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. ispartof: EBIOMEDICINE vol:50 pages:260-273 ispartof: location:Netherlands status: published
- Subjects :
- Lipopolysaccharides
Male
0301 basic medicine
Research paper
ALPHA-SYNUCLEIN
lcsh:Medicine
Research & Experimental Medicine
Mice
0302 clinical medicine
PARKINSONS-DISEASE
Neurons
lcsh:R5-920
SUBSTANTIA-NIGRA
Kinase
Chemistry
Neurodegeneration
Neurodegenerative Diseases
General Medicine
Immunohistochemistry
3. Good health
Neuroprotective Agents
TARGET
Medicine, Research & Experimental
030220 oncology & carcinogenesis
alpha-Synuclein
Cytokines
AUTOPHAGY
Microglia
lcsh:Medicine (General)
Life Sciences & Biomedicine
Tyrosine kinase
Pyridones
IMATINIB MESYLATE
Aggrephagy
Protein Aggregation, Pathological
Neuroprotection
General Biochemistry, Genetics and Molecular Biology
Cell Line
Proinflammatory cytokine
Protein Aggregates
03 medical and health sciences
Medicine, General & Internal
INFLAMMATION
General & Internal Medicine
Macroautophagy
KINASE
medicine
Animals
Humans
Neuroinflammation
Science & Technology
Interleukin-6
Autophagy
lcsh:R
C-ABL
MICROGLIAL ACTIVATION
medicine.disease
Disease Models, Animal
Oxidative Stress
Pyrimidines
030104 developmental biology
Cancer research
Biomarkers
Subjects
Details
- Language :
- English
- ISSN :
- 23523964
- Volume :
- 50
- Database :
- OpenAIRE
- Journal :
- EBioMedicine
- Accession number :
- edsair.doi.dedup.....df7ee5b37b511d2c908eab4d91f67245