Progranulin gene delivery protects dopaminergic neurons in a mouse model of Parkinson's disease

PLoS One. 2014 May 7;9(5):e97032. doi: 10.1371/journal.pone.0097032. eCollection 2014.


Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by tremor, rigidity and akinesia/bradykinesia resulting from the progressive loss of nigrostriatal dopaminergic neurons. To date, only symptomatic treatment is available for PD patients, with no effective means of slowing or stopping the progression of the disease. Progranulin (PGRN) is a 593 amino acid multifunction protein that is widely distributed throughout the CNS, localized primarily in neurons and microglia. PGRN has been demonstrated to be a potent regulator of neuroinflammation and also acts as an autocrine neurotrophic factor, important for long-term neuronal survival. Thus, enhancing PGRN expression may strengthen the cells resistance to disease. In the present study, we have used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD to investigate the possible use of PGRN gene delivery as a therapy for the prevention or treatment of PD. Viral vector delivery of the PGRN gene was an effective means of elevating PGRN expression in nigrostriatal neurons. When PGRN expression was elevated in the SNC, nigrostriatal neurons were protected from MPTP toxicity in mice, along with a preservation of striatal dopamine content and turnover. Further, protection of nigrostriatal neurons by PGRN gene therapy was accompanied by reductions in markers of MPTP-induced inflammation and apoptosis as well as a complete preservation of locomotor function. We conclude that PGRN gene therapy may have beneficial effects in the treatment of PD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Disease Models, Animal
  • Dopamine / genetics
  • Dopamine / metabolism
  • Dopaminergic Neurons / metabolism*
  • Dopaminergic Neurons / pathology
  • Gene Transfer Techniques
  • Genetic Therapy
  • Granulins
  • Humans
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins / genetics*
  • MPTP Poisoning / drug therapy*
  • MPTP Poisoning / genetics
  • MPTP Poisoning / pathology
  • Mice
  • Motor Activity / drug effects
  • Motor Activity / immunology
  • Parkinson Disease / drug therapy
  • Parkinson Disease / genetics*
  • Parkinson Disease / pathology
  • Progranulins


  • Granulins
  • Grn protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Progranulins
  • Dopamine

Grants and funding

This work was funded by the Michael J. Fox Foundation ( Neurodyn Inc., provided support in the form of salaries for all authors, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.