PITX3 polymorphism is associated with early onset Parkinson's disease

Bergman, Olle; Håkansson, Anna; Westberg, Lars; Nordenström, Kajsa; Belin, Andrea Carmine; Sydow, Olof; Olson, Lar̀s; Holmberg, Björn; Eriksson, Elias; Nissbrandt, Hans

doi:10.1016/j.neurobiolaging.2008.03.008

Cited by 57 publications

(69 citation statements)

References 18 publications

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“…Several developmental transcription factors, including Nurr1, Lmx1a/b, Engrailed 1, and Pitx3, remain expressed in mature DA neurons, and nucleotide polymorphisms in human genes encoding these factors have been associated with PD (11)(12)(13)(23)(24)(25)(26). Moreover, analysis of postmortem brain tissue has demonstrated down-regulation of Nurr1 and other key transcription factors in remaining DA neurons in PD, and significantly reduced Nurr1 and Pitx3 mRNA expression levels in peripheral blood cells in PD patients (14,15).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons

Kadkhodaei

Alvarsson

Schintu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

152

186

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Developmental transcription factors important in early neuron specification and differentiation often remain expressed in the adult brain. However, how these transcription factors function to mantain appropriate neuronal identities in adult neurons and how transcription factor dysregulation may contribute to disease remain largely unknown. The transcription factor Nurr1 has been associated with Parkinson's disease and is essential for the development of ventral midbrain dopamine (DA) neurons. We used conditional Nurr1 genetargeted mice in which Nurr1 is ablated selectively in mature DA neurons by treatment with tamoxifen. We show that Nurr1 ablation results in a progressive pathology associated with reduced striatal DA, impaired motor behaviors, and dystrophic axons and dendrites. We used laser-microdissected DA neurons for RNA extraction and next-generation mRNA sequencing to identify Nurr1-regulated genes. This analysis revealed that Nurr1 functions mainly in transcriptional activation to regulate a battery of genes expressed in DA neurons. Importantly, nuclear-encoded mitochondrial genes were identified as the major functional category of Nurr1-regulated target genes. These studies indicate that Nurr1 has a key function in sustaining high respiratory function in these cells, and that Nurr1 ablation in mice recapitulates early features of Parkinson's disease. NR4A2 | nuclear receptor | laser capture microdissection | RNA sequencing | orphan receptor U nder experimental conditions, somatic differentiated cells can undergo reprogramming into other cell types or induced pluripotent stem cells (1). This remarkable plasticity raises questions of how the differentiated cellular identity is maintained for extended periods in normal life (2). Of particular relevance is how neurons, which should retain their specific functions for decades in a human brain, stably maintain their unique differentiated properties, and how disrupted maintenance of the correct differentiated identity may be related to disease. Under embryonic development, signaling events induce the expression of transcription factors that combinatorially function to specify appropriate identities and differentiation of specific neuron types. Many of these transcription factors continue to be expressed in adult neurons as well; however, little is known of their functions in the adult brain, or the extent to which they contribute to the stability of the differentiated state (3).Degeneration of ventral midbrain (VMB) dopamine (DA) neurons, particularly neurons of the substantia nigra compacta (SNc), causes many of the characteristic symptoms in patients with Parkinson's disease (PD). PD is characterized by a progressive pathology involving the appearance of insoluble protein inclusions known as Lewy bodies and eventually the death of neurons. Several studies have indicated that loss of striatal DA and other dopaminergic properties cause symptoms in PD long before cell bodies within the SNc actually die (4). Thus, PD cell pathology may influence differentiated...

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Section: Discussionmentioning

confidence: 99%

Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons

Kadkhodaei

Alvarsson

Schintu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

152

186

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“…Interestingly, some of these studies also noted in the patients the preferential loss of a subset of SNc neurons that normally express high levels of BDNF (Parain et al, 1999;Howells et al, 2000). Moreover, several polymorphisms in noncoding regions of the PITX3 gene (which might alter PITX3 expression) are associated with idiopathic or early onset PD (Fuchs et al, 2009;Bergman et al, 2010;Haubenberger et al, 2011;Le et al, 2011), and one polymorphism in the promoter region of the human BDNF gene was associated with familial PD (Parsian et al, 2004). These findings, together with our results and the observation that conditional ablation of the BDNF gene during mouse development leads to the selective loss of a subset of TH ϩ neurons in the SNc, but not VTA (Baquet et al, 2005), raise the intriguing possibility that the rostrolateral (SNc) mdDA neuron subpopulation expressing high levels of BDNF is most affected by the loss of PITX3 in human PD patients and cannot be protected by the exogenous application of GDNF.…”

Section: Discussionmentioning

confidence: 99%

Pitx3 Is a Critical Mediator of GDNF-Induced BDNF Expression in Nigrostriatal Dopaminergic Neurons

Peng¹,

Aron²,

Klein³

et al. 2011

J. Neurosci.

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Ϫ/Ϫ mdDA neurons. Most importantly, only BDNF but not GDNF protects mdDA neurons against 6-hydroxydopamine-induced cell death in the absence of Pitx3. As the feedforward regulation of GDNF, Pitx3, and BDNF expression also persists in the adult rodent brain, our data suggest that the disruption of the regulatory interaction between these three factors contributes to the loss of mdDA neurons in Pitx3 Ϫ/Ϫ mutant mice and perhaps also in human PD.

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“…A number of recent genetic studies show that polymorphisms in the Pitx3 gene associates with early onset and familial forms of PD (Bergman, et al, 2010,Fuchs, et al, 2009,Le, et al, 2011 and Pitx3 knock-out mice show specific loss of SNC dopamine neurons (Hwang, et al, 2003,Nunes, et al, 2003,Smidt, et al, 2004. In our study Pitx3 immunoreactivity was not restricted to SNC neurons, and certainly was not restricted to those in the ventral SNC that are most vulnerable to PD.…”

Section: On a Cell-by-cell Basis Adult Human Dopamine Neurons Appearmentioning

confidence: 99%

Trophic factors differentiate dopamine neurons vulnerable to Parkinson's disease

Reyes

Double

et al. 2013

Neurobiology of Aging

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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

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PITX3 polymorphism is associated with early onset Parkinson's disease

Cited by 57 publications

References 18 publications

Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons

Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons

Pitx3 Is a Critical Mediator of GDNF-Induced BDNF Expression in Nigrostriatal Dopaminergic Neurons

Trophic factors differentiate dopamine neurons vulnerable to Parkinson's disease

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