Heterozygous GBA D490V and ATP13a2 mutations do not exacerbate pathological α-synuclein spread in the prodromal preformed fibrils model in young mice

Michaela E. Johnson, Liza Bergkvist, Lucas Stetzik, Jennifer A. Steiner, Lindsay Meyerdirk, Emily Schulz, Emily Wolfrum, Kelvin C. Luk, Daniel W. Wesson, Dimitri Krainc, Patrik Brundin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Autophagic dysregulation and lysosomal impairment have been implicated in the pathogenesis of Parkinson's disease, partly due to the identification of mutations in multiple genes involved in these pathways such as GBA, SNCA, ATP13a2 (also known as PARK9), TMEM175 and LRRK2. Mutations resulting in lysosomal dysfunction are proposed to contribute to Parkinson's disease by increasing α-synuclein levels, that in turn may promote aggregation of this protein. Here, we used two different genetic models–one heterozygous for a mutated form of the GBA protein (D409V), and the other heterozygous for an ATP13a2 loss-of-function mutation, to test whether these mutations exacerbate the spread of α-synuclein pathology following injection of α-synuclein preformed fibrils in the olfactory bulb of 12-week-old mice. Contrary to our hypothesis, we found that mice harboring GBA D409V+/− and ATP13a2+/− mutations did not have exacerbated behavioral impairments or histopathology (α-synuclein, LAMP2, and Iba1) when compared to their wildtype littermates. This indicates that in the young mouse brain, neither the GBA D409V mutation or ATP13a2 loss-of-function mutation accelerate the spread of α-synuclein pathology. As a consequence, we postulate that these mutations increase Parkinson's disease risk only by acting in one of the initial, upstream events in the Parkinson's disease pathogenic process. Further, the mutations, and the molecular pathways they impact, appear to play a less important role once the pathogenic process has been triggered and therefore do not specifically influence α-synuclein pathology spread.

Original languageEnglish (US)
Article number105513
JournalNeurobiology of Disease
Volume159
DOIs
StatePublished - Nov 2021

Keywords

  • ATP13a2
  • GBA
  • Olfactory bulb
  • Parkinson's disease
  • α-Synuclein preformed fibrils

ASJC Scopus subject areas

  • Neurology

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