The A30P α-synuclein mutation decreases subventricular zone proliferation

Xue Ming Zhang, Sabina Anwar, Yongsoo Kim, Jennifer Brown, Isabelle Comte, Huan Cai, Ning Ning Cai, Richard Wade-Martins, Francis G. Szele

Research output: Contribution to journalArticle

Abstract

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 Snca) modulates dopaminergic neurotransmission, and SNCA 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 SNCA familial PD point mutation on an Snca-/- background. We confirmed that the SNCA-A30P transgene recapitulates endogenous α-syn expression patterns and levels by immunohistochemical detection of endogenous α-syn in a wild-type mouse and transgenic SNCA-A30P α-syn protein in the forebrain. The number of SVZ stem cells (BrdU+GFAP+) was decreased in SNCA-A30P mice, whereas proliferating (phospho-histone 3+) cells were decreased in Snca-/- and even more so in SNCA-A30P mice. Similarly, SNCA-A30P mice had fewer Mash1+ transit-amplifying SVZ progenitor cells but Snca-/- mice did not. These data suggest the A30P mutation aggravates the effect of Snca loss in the SVZ. Interestingly, calbindin+ and calretinin (CalR)+ periglomerular neurons were decreased in both Snca-/-, and SNCA-A30P mice but tyrosine hydroxylase+ periglomerular OB neurons were only decreased in Snca-/- mice. Cell death decreased in the OB granule layer of Snca-/- and SNCA-A30P mice. In the same region, CalR+ numbers increased in Snca-/- and SNCA-A30P mice. Thus, α-syn loss and human A30P SNCA 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.

Original languageEnglish (US)
Article numberddz057
Pages (from-to)2283-2294
Number of pages12
JournalHuman Molecular Genetics
Volume28
Issue number14
DOIs
StatePublished - Jul 15 2019

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Synucleins
Lateral Ventricles
Mutation
Olfactory Bulb
Parkinson Disease
Neurogenesis
Calbindin 2
Transgenic Mice
Cell Death
Stem Cells
Bacterial Artificial Chromosomes
Neurons
Calbindins
alpha-Synuclein
Tyrosine 3-Monooxygenase
Interneurons
Bromodeoxyuridine
Prosencephalon
Transgenes
Point Mutation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Zhang, X. M., Anwar, S., Kim, Y., Brown, J., Comte, I., Cai, H., ... Szele, F. G. (2019). The A30P α-synuclein mutation decreases subventricular zone proliferation. Human Molecular Genetics, 28(14), 2283-2294. [ddz057]. https://doi.org/10.1093/hmg/ddz057
Zhang, Xue Ming ; Anwar, Sabina ; Kim, Yongsoo ; Brown, Jennifer ; Comte, Isabelle ; Cai, Huan ; Cai, Ning Ning ; Wade-Martins, Richard ; Szele, Francis G. / The A30P α-synuclein mutation decreases subventricular zone proliferation. In: Human Molecular Genetics. 2019 ; Vol. 28, No. 14. pp. 2283-2294.
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abstract = "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 Snca) modulates dopaminergic neurotransmission, and SNCA 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 SNCA familial PD point mutation on an Snca-/- background. We confirmed that the SNCA-A30P transgene recapitulates endogenous α-syn expression patterns and levels by immunohistochemical detection of endogenous α-syn in a wild-type mouse and transgenic SNCA-A30P α-syn protein in the forebrain. The number of SVZ stem cells (BrdU+GFAP+) was decreased in SNCA-A30P mice, whereas proliferating (phospho-histone 3+) cells were decreased in Snca-/- and even more so in SNCA-A30P mice. Similarly, SNCA-A30P mice had fewer Mash1+ transit-amplifying SVZ progenitor cells but Snca-/- mice did not. These data suggest the A30P mutation aggravates the effect of Snca loss in the SVZ. Interestingly, calbindin+ and calretinin (CalR)+ periglomerular neurons were decreased in both Snca-/-, and SNCA-A30P mice but tyrosine hydroxylase+ periglomerular OB neurons were only decreased in Snca-/- mice. Cell death decreased in the OB granule layer of Snca-/- and SNCA-A30P mice. In the same region, CalR+ numbers increased in Snca-/- and SNCA-A30P mice. Thus, α-syn loss and human A30P SNCA 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.",
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Zhang, XM, Anwar, S, Kim, Y, Brown, J, Comte, I, Cai, H, Cai, NN, Wade-Martins, R & Szele, FG 2019, 'The A30P α-synuclein mutation decreases subventricular zone proliferation', Human Molecular Genetics, vol. 28, no. 14, ddz057, pp. 2283-2294. https://doi.org/10.1093/hmg/ddz057

The A30P α-synuclein mutation decreases subventricular zone proliferation. / Zhang, Xue Ming; Anwar, Sabina; Kim, Yongsoo; Brown, Jennifer; Comte, Isabelle; Cai, Huan; Cai, Ning Ning; Wade-Martins, Richard; Szele, Francis G.

In: Human Molecular Genetics, Vol. 28, No. 14, ddz057, 15.07.2019, p. 2283-2294.

Research output: Contribution to journalArticle

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AU - Zhang, Xue Ming

AU - Anwar, Sabina

AU - Kim, Yongsoo

AU - Brown, Jennifer

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