Abstract
A number of transcription factors, including En1/2, Foxa1/2, Lmx1a/b, Nurr1, Otx2, and Pitx3, with key roles in midbrain dopaminergic (mDA) neuron development, also regulate adult mDA neuron survival and physiology. Mouse models with targeted disruption of some of these genes display several features reminiscent of Parkinson disease (PD), in particular the selective and progressive loss of mDA neurons in the substantia nigra pars compacta (SNpc). The characterization of these animal models has provided valuable insights into various mechanisms of PD pathogenesis. Therefore, the dissection of the mechanisms and survival signalling pathways engaged by these transcription factors to protect mDA neuron from degeneration can suggest novel therapeutic strategies. The work on En1/2-mediated neuroprotection also highlights the potential of protein transduction technology for neuroprotective approaches in PD.
Highlights
Parkinson disease (PD) is the second most common neurodegenerative disorder
One remarkable feature of the disease is that nonnigral dopaminergic neurons including midbrain dopaminergic (mDA) neurons in the ventral tegmental area (VTA), located in the vicinity of the substantia nigra pars compacta (SNpc) mDA neurons, are relatively spared
This review summarizes some aspects of the function of these developmental transcription factors in relation to PD
Summary
Parkinson disease (PD) is the second most common neurodegenerative disorder. The disease is characterized by a loss of midbrain dopaminergic (mDA) neurons in the substantia nigra pars compacta (SNpc) and the presence of α-synucleincontaining protein aggregates and termed Lewy bodies (and/or Lewy neurites) in affected neurons [1, 2]. The current view is that the slow and progressive death of SNpc mDA neurons remains asymptomatic until 30% of mDA neuron cell bodies and 50–60% of axonal terminals are lost [6] Over time, this loss results in severe dopamine (DA) deficiency in the striatum, leading to the cardinal motor symptoms including rest tremor, bradykinesia, rigidity, and postural instability. Mouse lines expressing PD-linked gene mutations recapitulate several features of PD pathogenesis but most of them do not present the selective and progressive loss of mDA neurons in the SNpc [24,25,26]. Major progress has recently been made in dissecting the genetic and signalling networks that control the generation of mDA neurons [27,28,29] These studies have revealed the crucial role of several transcription factors.
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