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

Prasannakumar Deshpande, Dani Flinkman, Ye Hong, Elena Goltseva, Valentina Siino, Lihua Sun, Sirkku Peltonen, Laura L Elo, Valtteri Kaasinen, Peter James, Eleanor T Coffey

Tutkimustuotos: LehtiartikkeliArtikkeliTieteellinenvertaisarvioitu

Abstrakti

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.

AlkuperäiskieliEnglanti
Sivut14217-14233
Sivumäärä17
JulkaisuFASEB Journal
Vuosikerta34
Numero11
DOI - pysyväislinkit
TilaJulkaistu - marraskuuta 2020
OKM-julkaisutyyppiA1 Julkaistu artikkeli, soviteltu

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