GDNF family ligands and neural stem cells in Parkinson's disease

Abstract

Parkinson's disease (PD) is a very common neurodegenerative disorder, characterized by a progressive degeneration of mainly nigrostriatal and mesolimbic dopaminergic neurons leading to tremor, rigidity and hypokinesia, the classical symptoms of the disease. Degeneration of noradrenergic neurons of the locus coeruleus are also involved in the progression of the disease, causing dementia and depression. The cause of the selective degeneration of specific populations of neurons in P1) is unknown, but it has been suggested that an increased oxidative stress is involved in the pathophysiology of the disease. The current treatment is based on the substitution of a dopamine precursor, L-DOPA, which was introduced more than 30 years ago. However, there is currently no way of halting the disease progress.

New therapeutic strategies are aiming at halting the neurodegenerative process or restoring the system by transplantation of fetal dopamine neurons. We have investigated the potential of the neurotrophic factors Glial cell line derived neurotrophic factor (GDN-F), Neurturin (NTN) and Persephin (PSP), belonging to the GDNF family of ligands, to exert neuroprotection and neuritogenesis on nigral dopamine and locus noradrenaline neurons. We saw both overlapping and differential effects of these ligands in their neurotrophic effects. The pronounced survival effects they all have make them good therapeutic candidates in the treatment of PD.

The inability of neurotrophic factors to pass the blood-brain barrier and their potent effects on other cell populations, causing severe side effects by systemic administration, makes it essential to achieve a localized sustained delivery of these proteins to the target cells. We have accomplished this in an ex vivo gene therapy approach by overexpressing GDNF family ligands in neural stem cells (NSCs). The NSCs differentiate upon grafting and adopt local phenotypes. Grafting of these NSCs in the target of the projecting dopaminergic neurons, the striatum, in a lesion model of PD protected many of the dopaminergic cells from degeneration and improved behavioral parameters in the treated animals.

In addition to the neuroprotective strategy in treatment of PD, as a replacement strategy we have managed to induce a dopaminergic fate in NSCs. We first overexpressed the transcription factor Nurr1 (required for the dopamine neurons in the substantia nigra) in proliferating NSCs and thereafter incubated the cells with soluble factors from type 1 astrocytes derived from the ventral mesencephalon. This resulted in an induction of more than 80% dopamine producing cells. These cells survived grafting to a low extent, but further improvement in survival must be achieved for these cells to become a realistic alternative to fetal dopaminergic cells.