Parkinson’s Disease and FGF Receptor in Gene Therapy

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Michal Stachowiak, K., Ph.D.

The State University School of New York at Buffalo, The Research Foundation of SUNY, Buffalo, NY

Abstract

While the field of movement disorders research has acceptable animal models for specific stages of parkinsonism (not PD), there is at present no such model that mimics progressive and specific degeneration of dopaminergic (DA) neurons; nor are we certain of the mechanisms leading to neuronal death. Dr. Michal K. Stachowiak (SUNY, Buffalo) plans to test the theory that basic fibroblast growth factor (bFGF) is depleted in PD and is a depletion specific to PD (unlike Lewy bodies, which are found in other disorders as well). Exactly what is the purpose of bFGF and how will it help parkinsonian rats when delivered by a viral vector? Increasing cell survival via this method could lead to new gene therapies aimed at supporting the survival or regeneration of multiple types of neuronal cells.

Progress Report (as of 8/2002)

Progress in treating (Parkinson’s Disease) PD is hampered by the lack of animal models that mimic progressive and specific degeneration of dopamine neurons observed in this disease in the brain region called Substantia Nigra, as well as by the lack of understanding the mechanisms leading to neuronal death. While a limited number of cases is associated with genetic defects (mutations in the synuclein or the parkin genes), the etiology of prevalent episodes of PD (unrelated to the parkin or synuclein mutations) remains unknown. These mechanisms could involve environmental neurotoxins, free radicals, as well as insufficient production of neurotrophic substances or disruption of the metabolic pathways that support neuronal survival. Recent studies have shown that specifically in PD the content of neurotrophic substance, fibroblast growth factor-2 (FGF-2) in s. nigra dopamine neurons becomes depleted prior to cell degeneration. Functions of FGF-2 in s. nigra and the significance of its depletion in PD patients are unknown.

Studies in our laboratory have revealed a new signaling mechanism we have named the Integrative Nuclear FGFR1 Signaling (INFS) pathway through which regulates growth and survival of neurons and astrocytes, two main cell types in the brain. This new pathway is initiated by the activation of the FGF-2 and FGF receptor-1 (FGFR1) genes followed by transfer of the full length FGFR1 and FGF-2 proteins directly from the cytoplasm to the cell nucleus. Nuclear FGFR1 regulates expression of different genes including the tyrosine hydroxylase (TH) responsible for the synthesis of dopamine, neurofilament gene (responsible for growth of neurons. INFS mediates both the axonal growth in cultured human and rat neurons. We have developed a protocol for delivering genes directly into the brain of adult rats using Polyetheleneimine (PEI)-as DNA carrier. We used this method to deliver mutated FGF receptor gene into s. nigra of the rat brain. This gene injection caused a delayed degeneration of s. nigra neurons similar to that observed in PD. These results indicate that FGF receptor signaling is essential for the long-term survival of dopamine neurons and that impaired FGF function may be a common underlying cause for the neuronal degeneration in PD. Using the above described gene transfer we have developed a new animal model for PD that should be useful for the development of new therapies.

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