Abstract
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.
Highlights
Progranulin (PGRN) is a secreted 593 amino acid multifunction protein that is highly conserved and found in a wide range of species ranging from eukaryotes to humans
PGRN mutations have been predominantly observed in FTLDU patients, the high degree of phenotypic variability associated with these mutations suggests its possible involvement in other neurodegenerative brain diseases, including Parkinson’s disease (PD) [7,8]
Intranigral Infusion of ND-602 Increases PGRN Expression in the SNC In order to assess the efficacy of this gene delivery approach, we examined immunolabeling for the reporter protein, green fluorescent protein (GFP), in the substantia nigra (SNC) of male C57Bl6 mice (3 months) approximately 4 weeks following unilateral intranigral infusion of the lentiviral construct, ND-602
Summary
Progranulin (PGRN) is a secreted 593 amino acid multifunction protein that is highly conserved and found in a wide range of species ranging from eukaryotes to humans. PGRN is widely distributed throughout the CNS where it is found primarily in neurons and microglia but has been detected, at much lower levels, in astrocytes and oligodendrocytes [1,2]. Mutations in PGRN were first identified in association with ubiquitin-positive frontotemporal lobar degeneration linked to chromosome 17q21 (FTLDU-17) [3,4,5]. A 50% reduction of functional PGRN (haploinsufficiency) leads to increased neuronal cell death in adult FTLD brains [6]. PGRN mutations have been predominantly observed in FTLDU patients, the high degree of phenotypic variability associated with these mutations suggests its possible involvement in other neurodegenerative brain diseases, including Parkinson’s disease (PD) [7,8]. Parkinsonism is displayed in some FTLD patients and is more common (up to 41%) in those patients with PGRN mutations [9,10]
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