Selective noradrenergic vulnerability in α-synuclein transgenic mice.
Classical pathological signs of Parkinson's disease (PD) include loss of dopaminergic neurons in substantia nigra (SN) and noradrenergic neurons in locus coeruleus (LC), and deposition of Lewy bodies rich in the presynaptic protein alpha-synuclein (ASYN). Mammalian genetic models based on ASYN overexpression, however, have generally not reproduced the profound dopaminergic deficit of PD and do not display classical PD phenotypes. In the current study we examined these catecholaminergic systems in transgenic (Tg) mice expressing the A53T mutant of human ASYN under the Prion promoter. Surprisingly we detected a substantial reduction in norepinephrine (NE), but not dopamine (DA), levels in spinal cord, olfactory bulb and striatum of aged (15-month-old), but not young (4-month-old) transgenic compared to control mice. In spinal cord and olfactory bulb of 15-month-old Tg mice there was an age-dependent decrease in tyrosine hydroxylase (TH) protein levels, which in spinal cord was accompanied by a decrease in TH-positive terminals detected by immunohistochemistry. There was no difference in the number of TH-positive neuron cell bodies in SN or LC between Tg and control mice. We conclude that aberrant ASYN, expressed in both SN and LC, induces preferential degeneration of noradrenergic terminals. These observations suggest that in mice the NE may be more vulnerable than the DA system to the toxic effects of aberrant alpha-synuclein, and are in line with the major damage to the NE system that occurs in patients with PD.
Sotiriou
Evangelos
E
Division of Basic Neurosciences, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece. esotir@bioacademy.gr
Vassilatis
Demetrios K
DK
Vila
Miquel
M
Stefanis
Leonidas
L
D000409:Alanine / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009638:Norepinephrine / Q000096:biosynthesis / Q000172:deficiency* / Q000633:toxicity; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D013912:Threonine / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics*
D051844:alpha-Synuclein; D013912:Threonine; D000409:Alanine; D009638:Norepinephrine