Objective/Rationale:
Progranulin (PGRN), a protein found in the brain, is thought to promote the survival and health of brain cells. Neurodyn Inc. has discovered PGRN to have disease-modifying effects in models of various neurodegenerative disorders, including Parkinson’s disease (PD) and has developed a method for enhancing expression of PGRN in the affected brain region. In this project, Neurodyn proposes to enhance PGRN expression in an animal model of PD as a protection against brain cell loss.
Project Description:
Neurodyn Inc. will administer its proprietary factor, designed to enhance PGRN expression, into the substantia nigra (the brain region affected in PD) of mice. Four weeks later, once PGRN expression has been elevated, animals will be exposed to the parkinsonism-inducing neurotoxin, MPTP. Animals will then be tested for locomotor dysfunction and the degree of dopamine cell loss in the brain will be assessed.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Despite the many advances that have been accomplished in PD therapy, there remains a major need for a neuroprotective therapy, capable of slowing or halting disease progression. The study described here is designed to both, demonstrate PGRNs potential as a therapeutic target in PD, and validate the effectiveness of Neurodyn’s proprietary approach as a neuroprotectant. This would have a significant impact on the quality of life for PD patients, possibly representing the difference between functional daily living and complete debilitation.
Anticipated Outcome:
Based on findings so far, the approach developed by Neurodyn Inc. will enhance the expression of PGRN in the substantian nigra of these animals. This is expected to provide some level of protection for these cells against the neurotoxin, MPTP. Thus, these animals are expected to display significantly less locomotor dysfunction and reduced cell loss. This will lead to further studies, designed towards the development of cell-type specific targeting as a potential therapeutant in PD.
Final Outcome
Progranulin (PGRN) is a secreted growth factor-like protein with diverse roles in normal and pathophysiological processes. Recent evidence has demonstrated its potential to act as a neuroprotectant. The ability of lentivirally delivered PGRN to protect against the development of Parkinsonism following a sub-chronic administration of MPTP to mice was evaluated at both the behavioral and neuropathological levels. PGRN treatment preserved normal locomotor activity and locomotor control following MPTP intoxication. Stereological cell counting, of both TH+ and Nissl+ cells in SNc demonstrated PGRN mediated preservation of these cell populations. Similarly, in striatum PGRN prevented loss of TH immunoreactivity, and preserved DAT immunoreactivity following exposure to MPTP. PGRN treatment resulted in a significant reduction in the level of microglial activation in SNc, following exposure to MPTP. Finally, PGRN treatment resulted in a significant reduction of post MPTP apoptosis in SNc assessed both morphologically (pyknotic nuclei) and by IHC to detect the activated form of caspase-3. This data strongly suggests that interventions designed to target PGRN may represent an effective therapeutic strategy, capable of slowing or halting disease progression in PD patients.