A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Protein synthesis is suppressed in sporadic and familial Parkinson's disease by LRRK2
Tekijät: Prasannakumar Deshpande, Dani Flinkman, Ye Hong, Elena Goltseva, Valentina Siino, Lihua Sun, Sirkku Peltonen, Laura L. Elo, Valtteri Kaasinen, Peter James, Eleanor T. Coffey
Kustantaja: WILEY
Julkaisuvuosi: 2020
Journal: FASEB Journal
Tietokannassa oleva lehden nimi: FASEB JOURNAL
Lehden akronyymi: FASEB J
Vuosikerta: 34
Numero: 11
Aloitussivu: 14217
Lopetussivu: 14233
Sivujen määrä: 17
ISSN: 0892-6638
eISSN: 1530-6860
DOI: https://doi.org/10.1096/fj.202001046R
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/50541196
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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
