Small molecule modulator of aggrephagy regulates neuroinflammation to curb pathogenesis of neurodegeneration

EBioMedicine. 2019 Dec;50:260-273. doi: 10.1016/j.ebiom.2019.10.036. Epub 2019 Nov 11.

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.

MeSH terms

  • Animals
  • Biomarkers
  • Cell Line
  • Cytokines / metabolism
  • Disease Models, Animal
  • Humans
  • Immunohistochemistry
  • Interleukin-6 / metabolism
  • Lipopolysaccharides / metabolism
  • Macroautophagy
  • Male
  • Mice
  • Microglia / drug effects
  • Microglia / metabolism
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / etiology*
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / physiopathology
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Oxidative Stress
  • Protein Aggregates / drug effects
  • Protein Aggregation, Pathological / drug therapy
  • Protein Aggregation, Pathological / metabolism*
  • Pyridones / pharmacology
  • Pyridones / therapeutic use
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • alpha-Synuclein / metabolism

Substances

  • Biomarkers
  • Cytokines
  • Interleukin-6
  • Lipopolysaccharides
  • Neuroprotective Agents
  • Protein Aggregates
  • Pyridones
  • Pyrimidines
  • alpha-Synuclein
  • PD 180970