title: Chronic deprivation of TrkB signaling leads to selective late-onset nigrostriatal dopaminergic degeneration.
abstract: The pathological hallmark of Parkinson's disease (PD) is a selective and progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). In the vast majority of cases the appearance of PD is sporadic, and its etiology remains unknown. Several postmortem studies demonstrate reduced levels of brain-derived neurotrophic factor (BDNF) in the SNc of PD patients. Application of BDNF promotes the survival of DA neurons in PD animal models. Here we show that BDNF signaling via its TrkB receptor tyrosine kinase is important for survival of nigrostriatal DA neurons in aging brains. Immunohistochemistry revealed that the TrkB receptor was expressed in DA neurons located in the SNc and ventral tegmental area (VTA). However, a significant loss of DA neurons occurred at 12-24 months of age only in the SNc but not in the VTA of TrkB hypomorphic mice in which the TrkB receptor was expressed at a quarter to a third of the normal amount. The neuronal loss was accompanied by a decrease in dopaminergic axonal terminals in the striatum and by gliosis in both the SNc and striatum. Furthermore, nigrostriatal DA neurons in the TrkB mutant mice were hypersensitive to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mitochondrial complex I inhibitor that selectively kills DA neurons. These results suggest that BDNF-to-TrkB signaling plays an important role in the long-term maintenance of the nigrostriatal system and that its deficiency may contribute to the progression of PD.
authors.affiliation: Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Maryna
authors.initials: M
authors.lastname: Baydyuk
authors.forename: Madeline T
authors.initials: MT
authors.lastname: Nguyen
authors.forename: Baoji
authors.initials: B
authors.lastname: Xu
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D020813:Receptor, trkB / Q000096:biosynthesis / Q000172:deficiency*; D015398:Signal Transduction / Q000235:genetics*; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
chemical_list: D020813:Receptor, trkB; D004298:Dopamine