title: GDNF signaling implemented by GM1 ganglioside; failure in Parkinson's disease and GM1-deficient murine model.
abstract: 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.
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94103-0555, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Hadaczek
authors.affiliation: Department of Neurology and Neurosciences MSB-H506, The State University of New Jersey, 185 South Orange Ave., Newark, NJ 07103, USA.
authors.forename: Gusheng
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94103-0555, USA.
authors.forename: Nitasha
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94103-0555, USA.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Ciesielska
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94103-0555, USA.
authors.forename: Krystof
authors.initials: K
authors.lastname: Bankiewicz
authors.affiliation: Department of Biostatistics/Epidemiology, New Jersey Medical School, Rutgers, The State University of New Jersey, 185 South Orange Ave., Newark, NJ 07103, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Davidow
authors.affiliation: Department of Neurology and Neurosciences MSB-H506, The State University of New Jersey, 185 South Orange Ave., Newark, NJ 07103, USA.
authors.forename: Zi-Hua
authors.initials: ZH
authors.lastname: Lu
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94103-0555, USA. Electronic address: john.forsayeth@ucsf.edu.
authors.forename: John
authors.initials: J
authors.lastname: Forsayeth
authors.affiliation: Department of Neurology and Neurosciences MSB-H506, The State University of New Jersey, 185 South Orange Ave., Newark, NJ 07103, USA. Electronic address: ledeenro@njms.rutgers.edu.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Ledeen
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005677:G(M1) Ganglioside / Q000031:analogs & derivatives / Q000378:metabolism; D005732:Gangliosides / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D010300:Parkinson Disease / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D005732:Gangliosides; D051100:Glial Cell Line-Derived Neurotrophic Factor; C086919:LIGA 20; D005677:G(M1) Ganglioside; D013110:Sphingosine
keywords: B4galnt1; GDNF; GM1 analogs; GM1 ganglioside; LIGA20; Neuroprotection; Parkinson's disease; RET signaling