تمایز عوامل وابسته بتغذیه نورونهای دوپامین آسیب پذیر برای بیماری پارکینسون

Recent studies suggest a variety of factors characterize substantia nigra neurons vulnerable to Parkinson's disease, including the transcription factors pituitary homeobox 3 (Pitx3) and orthodenticle homeobox 2 (Otx2) and the trophic factor receptor deleted in colorectal cancer (DCC), but there is limited information on their expression and localization in adult humans. Pitx3, Otx2, and DCC were immunohistochemically localized in the upper brainstem of adult humans and mice and protein expression assessed using relative intensity measures and online microarray data. Pitx3 was present and highly expressed in most dopamine neurons. Surprisingly, in our elderly subjects no Otx2 immunoreactivity was detected in dopamine neurons, although Otx2 gene expression was found in younger cases. Enhanced DCC gene expression occurred in the substantia nigra, and higher amounts of DCC protein characterized vulnerable ventral nigral dopamine neurons. Our data show that, at the age when Parkinson's disease typically occurs, there are no significant differences in the expression of transcription factors in brainstem dopamine neurons, but those most vulnerable to Parkinson's disease rely more on the trophic factor receptor DCC than other brainstem dopamine neurons.

By the onset of the motor symptoms of Parkinson's disease (PD) neuronal degeneration is still largely confined to a very restricted region of the substantia nigra, the ventral tier (Dickson et al., 2009). This is despite a more widespread deposition of α-synuclein in Lewy bodies and neurites at this early disease stage (Dickson et al., 2009). Identifying the cellular proteins and mechanisms that underlie this vulnerability is a priority. A number of studies on laboratory animals have identified candidate cellular proteins that appear to be expressed in restricted populations of brainstem dopamine neurons (Double et al., 2010) but confirmation of their expression in adult humans is generally lacking. Dopamine neurons in the brainstem are not confined to the substantia nigra pars compacta (SNC or A9 cell group) but are also located in the ventral tegmental area (VTA or A10 cell group) (Fig. 1). Approximately two-thirds are found in the SNC and one-third in the VTA (Halliday et al., 2012 and Smidt and Burbach, 2007) with these 2 types of dopamine neurons known to have molecular and genetic differences (Chung et al., 2005 and Greene et al., 2005). Within the SNC only the ventral subset of neurons degenerates by the onset of motor symptoms (Fearnley and Lees, 1991 and Gibb and Lees, 1991), the dorsal tier neurons being resistant to PD at this stage (Dickson et al., 2009).