Absence of Ret signaling in mice causes progressive and late degeneration of the nigrostriatal system

Support of ageing neurons by endogenous neurotrophic factors such
as glial cell line-derived neurotrophic factor (GDNF) and
brain-derived neurotrophic factor (BDNF) may determine whether the
neurons resist or succumb to neurodegeneration. GDNF has been
tested in clinical trials for the treatment of Parkinson disease
(PD), a common neurodegenerative disorder characterized by the loss
of midbrain dopaminergic (DA) neurons. BDNF modulates nigrostriatal
functions and rescues DA neurons in PD animal models. The
physiological roles of GDNF and BDNF signaling in the adult
nigrostriatal DA system are unknown. We generated mice with
regionally selective ablations of the genes encoding the receptors
for GDNF (Ret) and BDNF (TrkB). We find that Ret, but not TrkB,
ablation causes progressive and adult-onset loss of DA neurons
specifically in the substantia nigra pars compacta, degeneration of
DA nerve terminals in striatum, and pronounced glial activation.
These findings establish Ret as a critical regulator of long-term
maintenance of the nigrostriatal DA system and suggest conditional
Ret mutants as useful tools for gaining insights into the molecular
mechanisms involved in the development of PD.