Progranulin Gene Delivery Protects Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease

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.

Wild-type bone marrow transplant partially reverses neuroinflammation in progranulin-deficient mice

“…40 Another group recently reported that viral-mediated transfer of progranulin into substantia nigra partially protected from 1-methyl-4-phenyl-tetrahydropyridine dopaminergic neurotoxicity. 66 Since BM-derived cells, including microglia, express and secrete progranulin, here we tested the hypothesis that BMT would partially replace progranulin and its activity in cerebral cortex of Grn −/− mice. Our results showed that wt BMT partially reconstituted progranulin in the periphery and in cerebral cortex of Grn −/− mice, and that this was sufficient to reverse, either in part or in full, ex vivo and in vivo measures of exaggerated immune response that are characteristic of Grn −/− mouse cerebral cortex.…”

Genetics of FTLD: overview and what else we can expect from genetic studies

“…; Van Kampen et al . ). While the drug suberoylanilide hydroxamic acid was shown to increase GRN transcription, and alkalizing reagents and vacuolar ATPase inhibitors were shown to increase GRN levels in a post‐translational manner (Capell et al .…”

“…Moreover, exogenous GRN was able to rescue neurite branching and outgrowth in neurons lacking GRN and protected neurons from TDP-43-related neurotoxicity (Laird et al 2010;Gass et al 2012). In mouse models of Parkinson's disease (PD) and AD, the addition of GRN had neuroprotective effects suggesting beneficial effect of GRN up-regulation in multiple neurodegenerative disorders (Minami et al 2014;Van Kampen et al 2014). While the drug suberoylanilide hydroxamic acid was shown to increase GRN transcription, and alkalizing reagents and vacuolar ATPase inhibitors were shown to increase GRN levels in a posttranslational manner (Capell et al 2011;Cenik et al 2011), no GRN-modifying therapies are currently available to patients and alternative avenues to up-regulate GRN levels, especially in human brain, are clearly needed.…”

Copy number variability in Parkinson’s disease: assembling the puzzle through a systems biology approach

“…GRN encodes progranulin, a multifunction protein widely distributed throughout the central nervous system primarily in neurons and microglia, and a potent autocrine neurotrophic factor and regulator of neuroinflammation (Van Kampen et al 2014). Its loss-of-function mutations are known to be responsible for FTLDU-17 (ubiquitin-positive frontotemporal lobar degeneration linked to chromosome 17) and increase the risk for both Alzheimer’s and PD, suggesting important roles of progranulin in neurodegenerative processes (Chen et al 2015).…”

“…A deletion of GRN exons 1–11, resulting from a non-homologous recombination event, has been observed in a patient with typical GRN neuropathology, and in his sister presenting PD (Rovelet-Lecrux et al 2008). Moreover, it has been recently demonstrated that progranulin gene delivery protects dopaminergic neurons in a PD model, suggesting that GRN gene therapy may have beneficial effects in the treatment of PD (Van Kampen et al 2014). …”