Trophic factors differentiate dopamine neurons vulnerable to Parkinson's disease

Abstract

Recent studies suggest a variety of factors characterize substantia nigra neurons vulnerable to Parkinson's disease, including the transcription factors Pitx3 and Otx2 and the trophic factor receptor DCC, but there is limited information on their expression and localisation in adult humans. Pitx3, Otx2 and DCC were immunohistochemically localised 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 characterised 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.Key words: deleted in colorectal cancer; dopamine neurons; orthodenticle homeobox 2; Pitx3; substantia nigra Abbreviations: DCC= deleted in colorectal cancer; Otx2= orthodenticle homeobox 2; PD= Parkinson's disease; SNC= substantia nigra pars compacta; TH= tyrosine hydroxylase; VTA= ventral tegmental area Reyes et al. 3

Diversity matters – heterogeneity of dopaminergic neurons in the ventral mesencephalon and its relation to Parkinson's Disease

“…; Reyes et al . ), is involved in the generation and maintenance of the elaborate axonal arborization of these neurons. It is known that DCC regulates the guidance of SNc and VTA dopaminergic axons to the striatum via its interaction with netrin (Li et al .…”

Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner

“…DCC expression in dopamine neurons is high during early development and adolescence, in line with the maturational timeline of dopamine pathways. Interestingly, DCC expression is substantially lower during adulthood, suggesting that DCC signaling may play a different, more local, role in the adult brain (Osborne et al, 2005;Grant et al, 2007;Manitt et al, 2010;Reyes et al, 2013;Yetnikoff et al, 2007Yetnikoff et al, , 2010Yetnikoff et al, , 2011Yetnikoff et al, , 2013a. Using rodents, we showed that DCC signaling within the ventral tegmental area (VTA) dopamine neurons determines the extent of their innervation to the mPFC specifically during adolescence and, in turn, organizes the structure and function of mPFC local circuitries (Manitt et al, 2013).…”

Embryonic development of selectively vulnerable neurons in Parkinson’s disease

“…Although both SNC and VTA subtypes express Pitx3 during terminal differentiation 143, 144 and in aged humans, 206 only the SNC, in terms of survival, requires expression of Pitx3 . 68, 186, 207 Pitx3 supresses the intrinsic expression of En1 and thereby of posterior markers such as CCK in SNC DN.…”

“…Medial and paramedial mesodiencephalic floor plate progenitors generate DN in the SNC and VTA, respectively. Both express Pitx3 , 143, 144, 206 but knock-out of Pitx3 results in selective loss of SNC neurons, 68, 186, 207 so Pitx3 expression is required for the development of the SNC but not required for the VTA.…”