Abstract
The primary clinical motor symptoms of Parkinson’s disease (PD) result from loss of dopaminergic (DA) neurons in the substantia nigra (SN). Consequently, neurogenesis of this group of neurons in the adult brain has drawn considerable interest for the purpose of harnessing endogenous neurogenerative potential as well as devising better strategies for stem cell therapy for PD. However, the existence of adult neurogenesis for DA neurons within the SN remains controversial. To overcome technical and design limitations associated with previous studies, our group has developed a novel genetic mouse model for assessing adult nigral DA neurogenesis. This system utilizes transgenic mice that express a tamoxifen-activatable Cre recombinase (CreERT2) under the control of the neuronal progenitor cell promoters nestin or Sox2 leading to suppression of the DA neuron marker tyrosine hydroxylase (TH) via excision of exon 1 by flanking loxP sites in adult animals. This study reports that six months following initiation of a six week treatment with tamoxifen mice with nestin-mediated Th excision displayed a significant reduction in TH+ neurons in the SN. This finding indicates that nestin-expressing cells regenerate DA neurons within the SN of adult animals. Interestingly, no reduction was observed in TH+ cells following Sox2-mediated Th excision suggesting that a nestin+/SOX2− precursor cell population drives DA neurogenesis in the adult SN. This information represents a substantial leap in current knowledge of adult DA neurogenesis, will enable improved in vitro and in vivo modeling, as well as facilitate the harnessing of this process for therapeutic intervention for PD.
Highlights
Parkinson’s disease (PD) is the most common motor disorder and the second most prevalent neurodegenerative disease
If DA neurons were replenished in adult mice, there should be a gradual loss of tyrosine hydroxylase (TH) positive neurons in the substantia nigra (SN) over time following removal of the Th gene from precursor cells
No reduction in TH+ cells was observed in the SN of untreated nestinCRE-ERT2:Thlox/lox mice or tamoxifen-treated Sox2CRE-ERT2:Thlox/lox or Thlox/lox mice indicating that the loss in TH signal was due to Th gene excision and not the result of non-specific downregulation of Th expression by tamoxifen or the presence of the CRE transgene
Summary
Parkinson’s disease (PD) is the most common motor disorder and the second most prevalent neurodegenerative disease. PD motor dysfunction (rigidity, tremor, bradykinesia, and postural instability) results from loss of dopaminergic (DA) neurons in the substantia nigra (SN). A basic understanding of the mechanism for DA neuron loss remains elusive. Only symptomatic treatments exist for PD and none that address the underlying neurodegeneration. Determining whether DA neurons are replenished in the adult SN is fundamental to understanding the loss of these neurons during PD. One possibility is that suppression of adult DA neurogenesis could be a driving force toward PD. Exploiting endogenous neurogenesis could offer potential avenues for therapy as well as better inform stem cell transplantation efforts
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