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

2 Scopus citations

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

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Zhang, X. M., Anwar, S., Kim, Y., Brown, J., Comte, I., Cai, H., Cai, N. N., Wade-Martins, R., & 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