2. Academic Validation
  3. Small molecule modulator of aggrephagy regulates neuroinflammation to curb pathogenesis of neurodegeneration

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.
Suresh Sn 1,  Janhavi Pandurangi 2,  Ravi Murumalla 2,  Vidyadhara Dj 3,  Lakshmi Garimella 4,  Achyuth Acharya 2,  Shashank Rai 5,  Abhik Paul 6,  Haorei Yarreiphang 7,  Malini S Pillai 4,  Mridhula Giridharan 4,  James P Clement 6,  Phalguni Anand Alladi 7,  Taslimarif Saiyed 2,  Ravi Manjithaya 8
Affiliations

Affiliations

  • 1 Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, India; Centre for Brain Research (CBR), IISc, Bangalore, India.
  • 2 Centre for Cellular and Molecular Platforms (C-CAMP), Bangalore Life Sciences Cluster (BLiSC), Tata Institute of Fundamental Research, Bangalore, India.
  • 3 Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, India; Yale University, USA.
  • 4 Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, India.
  • 5 Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, India; MRC Laboratory of Molecular Biology, Cambridge, UK.
  • 6 Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, India.
  • 7 Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
  • 8 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.
PMID: 31727601 DOI: 10.1016/j.ebiom.2019.10.036
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.

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