The RET51/FKBP52 complex and its involvement in Parkinson disease.
The tyrosine kinase receptor RET51 is expressed in distinct families of neurons where it promotes different functions. FKBP52 is an immunophilin with neuroprotective effects on different kinds of neurons. In this paper, we demonstrate that RET51 activation by both glial cell line-derived neurotrophic factor (GDNF) and NGF triggers the formation of RET51/FKBP52 complex. The substitution of the tyrosine 905 of RET51, a key residue phosphorylated by both GDNF and NGF, disrupts the RET51/FKBP52 complex. NGF and GDNF have a functional role in dopaminergic (DA) neurons where RET51 and FKBP52 are expressed with a yet undefined function. To clarify if RET51/FKBP52 complex should exert its function in DA neurons, we used an indirect approach by screening the genes encoding for RET51 and FKBP52 in a group of 30 Parkinson's disease patients. The degeneration of DA neurons is the main feature of PD, which is associated to a complex multifactorial aetiology combining environmental, age-related and genetic factors. We found a compound heterozygous carrying two mutations in RET and FKBP52 that are sufficient to disrupt the RET51/FKBP52 complex, indicating its potential role in PD.
Fusco
Daniela
D
Unità di Genetica Medica, Policlinico Universitario S. Orsola-Malpighi, Bologna, Italy.
Vargiolu
Manuela
M
Vidone
Michele
M
Mariani
Elisa
E
Pennisi
Lucia Fiammetta
LF
Bonora
Elena
E
Capellari
Sabina
S
Dirnberger
Dietmar
D
Baumeister
Ralf
R
Martinelli
Paolo
P
Romeo
Giovanni
G
D000328:Adult; D002460:Cell Line; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020932:Nerve Growth Factor / Q000494:pharmacology; D010300:Parkinson Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D025941:Protein Interaction Mapping; D011494:Protein Kinases / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D055815:Young Adult
D051100:Glial Cell Line-Derived Neurotrophic Factor; D046912:Multiprotein Complexes; D020932:Nerve Growth Factor; D011494:Protein Kinases; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4