Genetic background influences LRRK2-mediated Rab phosphorylation in the rat brain.

Journal Article (Journal Article)

Pathogenic missense mutations in the leucine-rich repeat kinase 2 gene, encoding LRRK2, results in the upregulation of Rab10 and Rab12 phosphorylation in different cells and tissues. Here, we evaluate levels of the LRRK2 kinase substrates pT73-Rab10 and pS106-Rab12 proteins in rat brain tissues from different genetic backgrounds. Whereas lines of Sprague Dawley rats have equivalent levels of pT73-Rab10 and pS106-Rab12 similar to Lrrk2 knockout rats, Long-Evans rats have levels of pT73-Rab10 and pS106-Rab12 comparable to G2019S-LRRK2 BAC transgenic rats. Strong LRRK2 kinase inhibitors are ineffective at reducing pT73-Rab10 and pS106-Rab12 levels in the Sprague Dawley rats, but potently reduce pT73-Rab10 and pS106-Rab12 levels in Long-Evans rats. Oral administration of the PFE-360 LRRK2 kinase inhibitor fails to provide neuroprotection from dopaminergic neurodegeneration caused by rAAV2/1-mediated overexpression of A53T-αsynuclein in Sprague Dawley rats. These results highlight substantial differences in LRRK2-mediated Rab10 and Rab12 phosphorylation in commonly utilized rat genetic backgrounds and suggest LRRK2 may not play a central role in Rab phosphorylation or mutant αsynuclein toxicity in Sprague Dawley rats.

Full Text

Duke Authors

Cited Authors

  • Kelly, K; Chang, A; Hastings, L; Abdelmotilib, H; West, AB

Published Date

  • May 15, 2021

Published In

Volume / Issue

  • 1759 /

Start / End Page

  • 147372 -

PubMed ID

  • 33600829

Pubmed Central ID

  • PMC8006086

Electronic International Standard Serial Number (EISSN)

  • 1872-6240

Digital Object Identifier (DOI)

  • 10.1016/j.brainres.2021.147372

Language

  • eng

Conference Location

  • Netherlands