4.7 Article

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

Journal

FASEB JOURNAL
Volume 34, Issue 11, Pages 14217-14233

Publisher

WILEY
DOI: 10.1096/fj.202001046R

Keywords

biomarker; cellular mechanism; eEF2; LRRK2; neurodegeneration; Parkinson's disease

Funding

  1. Business Finland
  2. Michael J. Fox Foundation for Parkinson's Research (MJFF)
  3. Abo Akademi University
  4. Turku Graduate School of Biomedical Sciences
  5. MATTI Graduate School
  6. University of Lund

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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,Lrrk2knockdown orLrrk2knockout, 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 eIF2 alpha-S52(up arrow), eIF2s2-S2(down arrow), and eEF2-T57(up arrow) 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.

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