Heat shock protein-70 (Hsp-70) suppresses paraquat-induced neurodegeneration by inhibiting JNK and caspase-3 activation in Drosophila model of Parkinson's disease

PLoS One. 2014 Jun 2;9(6):e98886. doi: 10.1371/journal.pone.0098886. eCollection 2014.

Abstract

Parkinson's disease (PD) is one of the most common neurodegenerative disorders with limited clinical interventions. A number of epidemiological as well as case-control studies have revealed an association between pesticide exposure, especially of paraquat (PQ) and occurrence of PD. Hsp70, a molecular chaperone by function, has been shown as one of the modulators of neurological disorders. However, paucity of information regarding the protective role of Hsp70 on PQ-induced PD like symptoms led us to hypothesize that modulation of hsp70 expression in the dopaminergic neurons would improve the health of these cells. We took advantage of Drosophila, which is a well-established model for neurological research and also possesses genetic tools for easy manipulation of gene expression with limited ethical concern. Over-expression of hsp70 was found to reduce PQ-induced oxidative stress along with JNK and caspase-3 mediated dopaminergic neuronal cell death in exposed organism. Further, anti-apoptotic effect of hsp70 was shown to confer better homeostasis in the dopaminergic neurons of PQ-exposed organism as evidenced by their improved locomotor performance and survival. The study has merit in the context of human concern since we observed protection of dopaminergic neurons in PQ-exposed organism by over-expressing a human homologue of hsp70, HSPA1L, in these cells. The effect was parallel to that observed with Drosophila hsp70. These findings reflect the potential therapeutic applicability of hsp70 against PQ-induced PD like symptoms in an organism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Caspase 3 / metabolism*
  • Disease Models, Animal
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / enzymology
  • Dopaminergic Neurons / metabolism*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / drug effects
  • Drosophila melanogaster / enzymology
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / physiology
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Paraquat / toxicity
  • Parkinsonian Disorders / etiology
  • Parkinsonian Disorders / genetics
  • Parkinsonian Disorders / therapy*
  • Up-Regulation

Substances

  • Drosophila Proteins
  • HSP70 Heat-Shock Proteins
  • JNK Mitogen-Activated Protein Kinases
  • Caspase 3
  • Paraquat

Grants and funding

This work was supported by University Grants Commission (Grant number: EU249IV/2008/JUNE/318721 to AKS), Council of Scientific and Industrial Research (Grant number: 31/029(0199)/2008-EMR-1 to PP; 19-06/2011(i)EU-IV to HSC and NWP-UNDO/2012-17 to DKC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.