| Résumé: | <p>Parkinson's disease (PD) is associated with olfactory defects in addition to dopaminergic degeneration. Dopaminergic signalling is necessary for subventricular zone (SVZ) proliferation and olfactory bulb (OB) neurogenesis. Alpha-synuclein (α-syn or <em>Snca</em>) modulates dopaminergic neurotransmission, and <em>SNCA</em> mutations cause familial PD, but how α-syn and its mutations affect adult neurogenesis is unclear. To address this, we studied a bacterial artificial chromosome transgenic mouse expressing the A30P <em>SNCA</em> familial PD point mutation on an <em>Snca</em><sup>−/−</sup> background. We confirmed that the <em>SNCA-A30P</em>transgene recapitulates endogenous α-syn expression patterns and levels by immunohistochemical detection of endogenous α-syn in a wild-type mouse and transgenic <em>SNCA</em>-A30P α-syn protein in the forebrain. The number of SVZ stem cells (BrdU+GFAP+) was decreased in <em>SNCA</em>-<em>A30P</em> mice, whereas proliferating (phospho-histone 3+) cells were decreased in <em>Snca</em><sup>−/−</sup> and even more so in <em>SNCA</em>-<em>A30P</em> mice. Similarly, <em>SNCA</em>-<em>A30P</em> mice had fewer Mash1+ transit-amplifying SVZ progenitor cells but <em>Snca</em><sup>−/−</sup> mice did not. These data suggest the A30P mutation aggravates the effect of <em>Snca</em> loss in the SVZ. Interestingly, calbindin+ and calretinin (CalR)+ periglomerular neurons were decreased in both <em>Snca</em><sup>−/−</sup>, and <em>SNCA</em>-<em>A30P</em> mice but tyrosine hydroxylase+ periglomerular OB neurons were only decreased in <em>Snca</em><sup>−/−</sup> mice. Cell death decreased in the OB granule layer of <em>Snca</em><sup>−/−</sup> and <em>SNCA</em>-<em>A30P</em> mice. In the same region, CalR+ numbers increased in <em>Snca</em><sup>−/−</sup> and <em>SNCA</em>-<em>A30P</em> mice. Thus, α-syn loss and human A30P <em>SNCA</em> decrease SVZ proliferation, cell death in the OB and differentially alter interneuron numbers. Similar disruptions in human neurogenesis may contribute to the olfactory deficits, which are observed in PD.</p>
|
|---|