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(10,000 g, 30 min), 1.5 µl of supernatant was placed onto a nitrocellulose membrane (Bio-rad 162-147, 0.2 µm). Non-specific binding sites were saturated with 50 mM Tris buffer containing 2% bovine serum albumin. The protein was revealed using, in succession, a mouse monoclonal antibody to TH (10 ng/ml; Boehringer Mannheim), a 125I-labeled protein A (S.A: 1.11x 10-9 Bq/mg, 1850 Bq/ml, Amersham) and 3H-hyperfilms (Amersham). The radioimmunochemical labeling was calibrated using a scale of standard TH protein (extracted from adult rat adrenals and diluted in homogenates of cerebellum). One U of TH (UTH) is defined as the mean TH protein content of 10 µg (wet weight) of adult rat adrenal gland. Optical density measurements were converted into UTH/mg tissue by reference to the standards. Each reading provided the surface area (mm2) of the dot and the TH tissue concentration (UTH/mg tissue). Using the surface area and the TH tissue concentration, the amount of TH (UTH) in the region of interest was calculated and normalized by expressing

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The work described here was supported by the Institut National de la Santé et de la Recherché Médicale, le Centre National de la Recherche Scientifique et Rhone Alpes Région.

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the amount of TH as a percentage of values in the control rats.

Imagemaster Labscan V-3.00 (Pharmacia Biotech, Dzahini et al., 2010).

**7.12 Immunoprecipitation of TH enzyme** 

**8. Acknowledgment** 

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**12** 

 *Australia* 

**Activity-Dependent Regulation of the Dopamine** 

The motor symptoms of Parkinson's disease (PD) are caused by degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and the resulting depletion of DA signaling in their target structure, the dorsal striatum (the nigrostriatal pathway). PD motor symptoms are successfully alleviated by systemic administration of a blood-brain barrier permeable DA precursor (levodopa) or DA receptor agonists (Olanow et al. 2001), however these treatments are marred by side-effects in some patients (Wood 2010), and increasingly unreliable response and shortened duration of effect coupled with the emergence of dyskinesias in most patients (Stocchi et al. 2010, Stocchi & Marconi 2010). These problems probably arise from loss of physiological storage, release and reuptake of nigrostriatal DA and ensuing down-stream changes in post-synaptic signaling, and from increased DA signaling in structures outside the nigrostriatal pathway, especially when D2 agonists are used. Targeted (nigrostriatal) reconstruction of physiological DA signaling, aimed at restoring nigrostriatal DA transmission to at least the level at disease outset, ought to alleviate PD motor symptoms without side-effects. However, attempts to achieve this by replacing SNc DA cells through transplantation or endogenous repair are often hampered by poor acquisition and maintenance of the DA phenotype in the microenvironment of the adult SNc (Brundin et al. 2000, Courtois et al. 2010, Torres et al. 2005, Bauer et al. 2000).

There is evidence that expression of tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis) by adult SNc and midbrain neurons is pliable. TH is down-regulated in cells that survive exposure to neurotoxins [6-hydroxy-dopamine (6-OHDA) or 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP)], and can be up-regulated again, presumably in these same cells, by glial-derived neurotrophic factor (GDNF) (Bjorklund *et al.* 1997, Bowenkamp *et al.* 1996, Gash *et al.* 1996, Sauer & Oertel 1994). There is also a degree of spontaneous recovery in the number of TH immunoreactive (TH+) SNc cells following 6- OHDA, which occurs coincidentally with a decrease in the number of SNc cells that are not immunoreactive against TH (TH-) (Stanic *et al.* 2003), implying acquisition of DA phenotype by extant cells. The DA phenotype of SNc neurons also appears to be regulated in an activity-dependent way. Reduced SNc TH expression following striatal infarct is blocked by

**1. Introduction** 

**Phenotype in the Adult Substantia Nigra:** 

Mal Horne, Kate Lord and Tim Aumann

*Florey Neuroscience Institutes, The University of Melbourne,* 

**Prospects for Treating Parkinson's Disease** 

