GDNF signaling implemented by GM1 ganglioside; failure in Parkinson's disease and GM1-deficient murine model

GDNF is indispensible for adult catecholaminergic neuron survival, and failure of GDNF signaling has been linked to loss of dopaminergic neurons in Parkinson's disease (PD). This study demonstrates attenuated GDNF signaling in neurons deficient in ganglio-series gangliosides, and restoration of such signaling with LIGA20, a membrane permeable analog of GM1. GM1 is shown to associate in situ with GFRα1 and RET, the protein components of the GDNF receptor, this being necessary for assembly of the tripartite receptor complex. Mice wholly or partially deficient in GM1 due to disruption of the B4galnt1 gene developed PD symptoms based on behavioral and neuropathological criteria which were largely ameliorated by gene therapy with AAV2-GDNF and also with LIGA20 treatment. The nigral neurons of PD subjects that were severely deficient in GM1 showed subnormal levels of tyrosine phosphorylated RET. Also in PD brain, GM1 levels in the occipital cortex, a region of limited PD pathology, were significantly below age-matched controls, suggesting the possibility of systemic GM1 deficiency as a risk factor in PD. This would accord with our finding that mice with partial GM1 deficiency represent a faithful recapitulation of the human disease. Together with the previously demonstrated age-related decline of GM1 in human brain, this points to gradual development of subthreshold levels of GM1 in the brain of PD subjects below that required for effective GDNF signaling. This hypothesis offers a dramatically different explanation for the etiology of sporadic PD as a manifestation of acquired resistance to GDNF. •The new mouse model of PD based on deficiency of GM1 manifests deficient GDNF neuroprotective signaling.•Similar deficiency in GDNF signaling is described in brains of PD subjects, which were also deficient in GM1.•GM1 is necessary for the formation of the GDNF receptor complex; we show that GM1 is an integral part of this complex.•LIGA20, a membrane permeable analog of GM1, rectified the impaired GDNF signaling both in vivo and in vitro.•GM1 in the occipital cortex of PD subjects was significantly below controls (p=0.002, n=13/13); systemic effect.