RET signaling does not modulate MPTP toxicity but is required for regeneration of dopaminergic axon terminals

Abstract

Parkinson's disease ͉ 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ͉ glial cell-line-derived neurotrophic factor ͉ neuroprotection

Dopamine-depletion and increased α-synuclein load induce degeneration of cortical cholinergic fibers in mice

“…The total numbers of ChAT-positive neurons and total number of neurons in the NBM-SI were counted by using the optical fractionator, an unbiased stereological technique of cell counting (StereoInvestigator, MBF Bioscience, Magdeburg), blinded for experimental grouping [23,28]. Two-way ANOVA followed by Newman-Keuls post hoc test was carried out (R software packages, version 2.8.0, R Development Core Team 2008, Vienna, Austria.).…”

“…For quantification of cholinergic neurons in the SI-NBM, freefloating, double-labeling, peroxidase based immunohistochemistry was performed [23,24]. Visualization of acetyl-cholinesterase (AChE) fibers was carried out according to the method of Hedreen et al [25], with slight modifications [26].…”

“…For immunohistochemistry and histochemistry, brains of eight mice from each subgroup were fixed and sectioned as we described previously [23].…”

Expression of GDNF receptors GFRα1 and RET is preserved in substantia nigra pars compacta of aging Asian Indians

“…Thus, RET expression is required for maturation of dopaminergic neurons. Although it does not amend MPTP toxicity, RET signaling is essential for regeneration of dopaminergic neurons (Kowsky et al, 2007). Preservation of RET expression in the human SNpc in PD (Walker et al, 1998) indicates that the treatment of diseased nigrostriatal system may be possible with GDNF or Neurturin.…”

Gdf-15 deficiency does not alter vulnerability of nigrostriatal dopaminergic system in MPTP-intoxicated mice

“…In contrast to the drastic permanent lesion exerted by 6-OHDA, the MPTP lesion is transient, allowing recovery of the system after several months (Beal 2001;Schober 2004;Bové and Perier 2012). The recovery phase has also been shown to be dependent on neurotrophic support, for example, on the presence of the Gdnf ligand and receptor system (Kowsky et al 2007;Kells et al 2010). …”