Effect of α-synuclein on the promoter activity of tyrosine hydroxylase gene

Loss of dopaminergic neurons and α-synuclein accumulation are the two major pathological hallmarks of Parkinson’s disease (PD). Currently, the mechanisms governing depletion of dopamine content and α-synuclein accumulation are not well understood. We showed that the oxysterol 27-hydroxycholesterol (27-OHC) reduces the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, and increases α-synuclein levels in SH-SY5Y cells. However, the cellular mechanisms involved in 27-OHC effects were not elucidated. Here, we demonstrate that 27-OHC regulates TH and α-synuclein expression levels through the estrogen receptors (ER) and liver X receptors (LXR). We specifically show that inhibition of ERβ mediates 27-OHC-induced decrease in TH expression, an effect reversed by the ER agonist estradiol. We also show that 27-OHC and the LXR agonist GW3965 increase α-synuclein while the LXR antagonist ECHS significantly attenuated the 27-OHC-induced increase in α-synuclein expression. We further demonstrate that LXRβ positively regulates α-synuclein expression and 27-OHC increases LXRβ-mediated α-synuclein transcription. Our results demonstrate the involvement of two distinct pathways that are involved in the 27-OHC regulation of TH and α-synuclein levels. Concomitant activation of ERβ and inhibition of LXRβ prevent 27-OHC effects and may therefore reduce the progression of PD by precluding TH reduction and α-synuclein accumulation.

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“…2002; Zhou and Freed 2005) as well as decreased TH expression (Yu et al. 2004; Gao et al. 2007) and activity (Perez et al.…”

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confidence: 99%

RETRACTED: The oxysterol 27‐hydroxycholesterol regulates α‐synuclein and tyrosine hydroxylase expression levels in human neuroblastoma cells through modulation of liver X receptors and estrogen receptors–relevance to Parkinson’s disease

Marwarha

Rhen

Schommer

et al. 2011

Journal of Neurochemistry

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“…The physiological role of nuclear a-Syn remains elusive, and only few data have demonstrated that a-Syn affects gene expression and regulates TH expression in both cultured cells and brain of aged monkeys (Chu and Kordower, 2007;Gao et al, 2007;Wu et al, 2009). …”

Section: [ ( ) T D $ F I G ]mentioning

confidence: 99%

Different sub-cellular localization of alpha-synuclein in the C57BL\6J mouse's central nervous system by two novel monoclonal antibodies

Vivacqua

Casini

Vaccaro

et al. 2011

Journal of Chemical Neuroanatomy

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“…Whereas the physiological function of α-synuclein remains to be fully characterized [63-65]. Several studies have established that interaction of α-synuclein and TH is of functional relevance to dopaminergic neurotransmission and the pathophysiology of PD [49, 66, 67]. Indeed, α-synuclein gene mutations and PD pathogenesis are well documented [49].…”

Section: Introductionmentioning

confidence: 99%

A Synopsis on the Role of Tyrosine Hydroxylase in Parkinson’s Disease

Tabrez¹,

Jabir²,

Shakil³

et al. 2012

CNSNDDT

128

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Parkinson's disease (PD) is a common chronic progressive neurodegenerative disorder in elderly people. A consistent neurochemical abnormality in PD is degeneration of dopaminergic neurons in substantia nigra pars compacta, leading to a reduction of striatal dopamine (DA) levels. As tyrosine hydroxylase (TH) catalyses the formation of L-dihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of DA, the disease can be considered as a TH-deficiency syndrome of the striatum. Problems related to PD usually build up when vesicular storage of DA is altered by the presence of either α-synuclein protofibrils or oxidative stress. Phosphorylation of three physiologically-regulated specific sites of N-terminal domain of TH is vital in regulating its kinetic and protein interaction. The concept of physiological significance of TH isoforms is another interesting aspect to be explored further for a comprehensive understanding of its role in PD. Thus, a logical and efficient strategy for PD treatment is based on correcting or bypassing the enzyme deficiency by the treatment with L-DOPA, DA agonists, inhibitors of DA metabolism or brain grafts with cells expressing a high level of TH. Neurotrophic factors are also attracting the attention of neuroscientists because they provide the essential neuroprotective and neurorestorative properties to the nigrostriatal DA system. PPAR-γ, a key regulator of immune responses, is likewise a promising target for the treatment of PD, which can be achieved by the use of agonists with the potential to impact the expression of pro- and anti-inflammatory cytokines at the transcriptional level in immune cells via expression of TH. Herein, we review the primary biochemical and pathological features of PD, and describe both classical and developing approaches aimed to ameliorate disease symptoms and its progression.

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Effect of α-synuclein on the promoter activity of tyrosine hydroxylase gene

Cited by 28 publications

References 16 publications

RETRACTED: The oxysterol 27‐hydroxycholesterol regulates α‐synuclein and tyrosine hydroxylase expression levels in human neuroblastoma cells through modulation of liver X receptors and estrogen receptors–relevance to Parkinson’s disease

RETRACTED: The oxysterol 27‐hydroxycholesterol regulates α‐synuclein and tyrosine hydroxylase expression levels in human neuroblastoma cells through modulation of liver X receptors and estrogen receptors–relevance to Parkinson’s disease

Different sub-cellular localization of alpha-synuclein in the C57BL\6J mouse's central nervous system by two novel monoclonal antibodies

A Synopsis on the Role of Tyrosine Hydroxylase in Parkinson’s Disease

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