Protein synthesis is suppressed in sporadic and familial Parkinson’s disease by LRRK2

Research output: Contribution to journalArticle

Abstract

Gain of function LRRK2-G2019S is the most frequent mutation found in familial and sporadic Parkinson's disease. It is expected therefore that understanding the cellular function of LRRK2 will provide insight on the pathological mechanism not only of inherited Parkinson's, but also of sporadic Parkinson's, the more common form. Here, we show that constitutive LRRK2 activity controls nascent protein synthesis in rodent neurons. Specifically, pharmacological inhibition of LRRK2, Lrrk2 knockdown or Lrrk2 knockout, all lead to increased translation. In the rotenone model for sporadic Parkinson's, LRRK2 activity increases, dopaminergic neuron translation decreases, and the neurites atrophy. All are prevented by LRRK2 inhibitors. Moreover, in striatum and substantia nigra of rotenone treated rats, phosphorylation changes are observed on eIF2α-S52(↑), eIF2s2-S2(↓), and eEF2-T57(↑) in directions that signify protein synthesis arrest. Significantly, translation is reduced by 40% in fibroblasts from Parkinson's patients (G2019S and sporadic cases alike) and this is reversed upon LRRK2 inhibitor treatment. In cells from multiple system atrophy patients, translation is unchanged suggesting that repression of translation is specific to Parkinson's disease. These findings indicate that repression of translation is a proximal function of LRRK2 in Parkinson's pathology.

Details

Authors
Organisations
External organisations
  • Åbo Akademi University
  • Turku University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology

Keywords

  • biomarker, cellular mechanism, eEF2, LRRK2, neurodegeneration, Parkinson's disease
Original languageEnglish
Pages (from-to)14217-14233
Number of pages17
JournalFASEB Journal
Volume34
Issue number11
Early online date2020
Publication statusPublished - 2020 Nov
Publication categoryResearch
Peer-reviewedYes