Neurotrophic factors and Parkinson disease
Parkinson's disease (PD) is the most common neurodegenerative movement disorder, clinically characterized by resting tremor, rigidity, postural imbalance and bradykinesia. The underlying pathological event in PD is the progressive loss of dopaminergic (DA) neurons in the Substantia Nigra pars compacta (SNpc) and their projections to the striatum. These pathologies are often accompanied by intracytoplasmic proteinaceous inclusions termed Lewy bodies and by neuroinflammatory processes. The molecular mechanisms underlying the selective degeneration of the nigrostriatal pathway in PD patients are not well understood.
Endogenous neurotrophic factors maintain target innervations and cell survival during postnatal life. Declining production of a neurotrophic factor or impaired signal transduction in ageing neurons may contribute to pathological neurodegeneration. Glial cell line-derived neurotrophic factor (GDNF) protects DA neurons from the effects of neurotoxins and it is currently tested in clinical trials (using different delivery systems) with the hope that it will ameliorate Parkinson’s disease symptoms. Brain-derived neurotrophic factor (BDNF) is another neurotrophic factor which rescues dopaminergic neurons in PD animal models.
To investigate the physiological requirements for GDNF and BDNF in establishing and maintaining the nigrostriatal pathway, we generated mice with regionally selective ablations of the receptors for GDNF (termed Ret) and BDNF (termed TrkB). We found that Ret, but not TrkB, signaling regulates long-term maintenance of the nigrostriatal dopaminergic system. Ret ablation in midbrain DA neurons causes progressive and late loss of DA neurons in the SNpc, degeneration of DA nerve terminals in the striatum, pronounced reactive gliosis, and reduced levels of evoked dopamine release (Kramer et al., 2007).
Together, these data establish Ret as an important signaling receptor for nigrostriatal DA system preservation and suggest conditional Ret mutants as an interesting model to study early PD-related pathologies. In collaboration with Professor Jörg Schulz (University of Göttingen) we further showed that endogenous Ret signaling facilitates the regeneration of dopaminergic axon terminals in a neurotoxin (MPTP) model for PD (Kowsky et al., 2007).
Genetic experiments were performed to investigate whether chronic GDNF deprivation stress in Ret mutant mice makes nigral DA neurons more susceptible to other cellular stresses ultimately leading to a more complete destruction of the nigrostriatal pathway. The PD-associated gene DJ-1 encodes a small, single domain protein that is thought to respond to oxidative stress and to protect neurons from environmental toxins. While inactivation of DJ-1 in humans causes PD, animal models lacking DJ-1 show no overt DA neuron degeneration in the SN. Aging mice that lack DJ-1 and Ret lose more DA neurons in the SN as compared with aging mice that lack only Ret. We suggest that understanding the molecular connections between trophic signaling, cellular stress and aging could facilitate the identification of new therapeutic approaches for Parkinson Disease (Aron et al., 2010).
