The A30P α-synuclein mutation decreases subventricular zone proliferation
<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...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Oxford University Press
2019
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| _version_ | 1797103837832544256 |
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| author | Zhang, X-M Anwar, S Kim, Y Brown, J Comte, I Cai, H Cai, N-N Wade-Martins, R Szele, FG |
| author_facet | Zhang, X-M Anwar, S Kim, Y Brown, J Comte, I Cai, H Cai, N-N Wade-Martins, R Szele, FG |
| author_sort | Zhang, X-M |
| collection | OXFORD |
| description | <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> |
| first_indexed | 2024-03-07T06:25:39Z |
| format | Journal article |
| id | oxford-uuid:f4347a8c-2fe4-4c31-8278-a877a84e539d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:25:39Z |
| publishDate | 2019 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:f4347a8c-2fe4-4c31-8278-a877a84e539d2022-03-27T12:18:07ZThe A30P α-synuclein mutation decreases subventricular zone proliferationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f4347a8c-2fe4-4c31-8278-a877a84e539dEnglishSymplectic Elements at OxfordOxford University Press2019Zhang, X-MAnwar, SKim, YBrown, JComte, ICai, HCai, N-NWade-Martins, RSzele, FG<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> |
| spellingShingle | Zhang, X-M Anwar, S Kim, Y Brown, J Comte, I Cai, H Cai, N-N Wade-Martins, R Szele, FG The A30P α-synuclein mutation decreases subventricular zone proliferation |
| title | The A30P α-synuclein mutation decreases subventricular zone proliferation |
| title_full | The A30P α-synuclein mutation decreases subventricular zone proliferation |
| title_fullStr | The A30P α-synuclein mutation decreases subventricular zone proliferation |
| title_full_unstemmed | The A30P α-synuclein mutation decreases subventricular zone proliferation |
| title_short | The A30P α-synuclein mutation decreases subventricular zone proliferation |
| title_sort | a30p α synuclein mutation decreases subventricular zone proliferation |
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