Absolute requirement of GDNF for adult catecholaminergic neuron survival (Nat Neurosci, 2008, 11:755-761)

報告日期: 2008/12/12
報告時間: 17:10/18:00
報告學生: 劉威廷
講評老師: 莊季瑛
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/971212-3.pdf

Absolute requirement of GDNF for adult catecholaminergic neuron survival

Alberto Pascual, Marı´a Hidalgo-Figueroa, Jose´ I Piruat, C Oscar Pintado,

Raquel Go´mez-Dı´az & Jose´ Lo´ pez-Barneo

Nat Neurosci 11, 755-761, 2008

 

Speaker: Wei-Ting Liu (劉威廷)

Commentator: Jih-Ing Chuang, Ph.D. (莊季瑛 老師)

Time: 17:10-18:00, Dec 5, 2008

Place: room 602

 

Abstract

   Glial cell line-derived neurotrophic factor (GDNF), a member of the TGF-b superfamily, is a potent survival factor for mesencephalic dopaminergic neurons in experimental rodent and primate animal model of Parkinson’s disease and has shown promise in some clinical trials. However, the actual physiological function of endogenous GDNF in development and maintenance of dopaminergic neuron has remained unclear. Furthermore, previous studies have failed to demonstrate a substantial role of endogenous GDNF in adult dopaminergic neuron survival. To avoid the developmental compensatory mechanisms masking its true physiologic action, the authors generated conditional GDNF-null mice to suppress GDNF expression in adulthood by using the tamoxifen inducible CRE recombinase system. The fact that the conditional knock-out mice showing less 20% than normal GDNF alleles were still able to produce about 40% of the normal amount of GDNF suggested a compensatory upregulation of Gdnf gene transcription in the remaining functional alleles. Surprisingly, the authors found that the conditional knock-out mice 7 months after Gdnf deletion showed selective and extensive catecholaminergic neuronal death, about 60-70% of substantia nigra and ventral tegmental area dopaminergic neuron were missing, whereas noradrenergic neurons in the locus coeruleus were almost completely absent. Nevertheless, GABAergic and cholinergic neurons appear to be unaffected. In the meantime, the neurochemical and histological alterations in GDNF-deprived mice induced the progressive appearance of behavioral motor disturbance. These results suggested that the endogenous GDNF was absolutely required for the survival of adult catecholaminergic neuron and should serve to rekindle efforts to use this protein in the clinic.

 

References

1.   Lin, L.F., et al. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260, 1130–1132, 1993.

2.   Lang, A.E. et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann. Neurol. 59, 459–466, 2006.

3.   Check, E. Second chance. Nat. Med. 13, 770–771, 2007.