A possible pathophysiological role of tyrosine hydroxylase in Parkinson's disease suggested by postmortem brain biochemistry: a contribution for the special 70th birthday symposium in honor of Prof. Peter Riederer.
Postmortem brain biochemistry has revealed that the main symptom of movement disorder in Parkinson's disease (PD) is caused by a deficiency in dopamine (DA) at the nerve terminals of degenerating nigro-striatal DA neurons in the striatum. Since tyrosine hydroxylase (TH) is the rate-limiting enzyme for the biosynthesis of DA, TH may play an important role in the disease process of PD. DA regulated by TH activity is thought to interact with α-synuclein protein, which results in intracellular aggregates called Lewy bodies and causes apoptotic cell death during the aging process. Human TH has several isoforms produced by alternative mRNA splicing, which may affect activation by phosphorylation of serine residues in the N-terminus of TH. The activity and protein level of TH are decreased to cause DA deficiency in the striatum in PD. However, the homo-specific activity (activity/enzyme protein) of TH is increased. This increase in TH homo-specific activity suggests activation by increased phosphorylation at the N-terminus of the TH protein for a compensatory increase in DA synthesis. We recently found that phosphorylation of the N-terminal portion of TH triggers proteasomal degradation of the enzyme to increase TH turnover. We propose a hypothesis that this compensatory activation of TH by phosphorylation in the remaining DA neurons may contribute to a further decrease in TH protein and activity in DA neurons in PD, causing a vicious circle of decreasing TH activity, protein level and DA contents. Furthermore, increased TH homo-specific activity leading to an increase in DA may cause toxic reactive oxygen species in the neurons to promote neurodegeneration.
Department of Physiology, Fujita Health University School of Medicine, Toyoake, Aichi, 470-1192, Japan.
Akira
A
Nakashima
Akira
A
Ota
Yoko S
YS
Kaneko
Keiji
K
Mori
Hiroshi
H
Nagasaki
Toshiharu
T
Nagatsu
D001921:Brain / Q000201:enzymology* / Q000473:pathology; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D006801:Humans; D010300:Parkinson Disease / Q000473:pathology*; D011180:Postmortem Changes; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D014446:Tyrosine 3-Monooxygenase