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

Deshpande, Prasannakumar ; Flinkman, Dani LU ; Hong, Ye ; Goltseva, Elena LU ; Siino, Valentina LU ; Sun, Lihua ; Peltonen, Sirkku ; Elo, Laura L. ; Kaasinen, Valtteri and James, Peter LU orcid , et al. (2020) In FASEB Journal 34(11). p.14217-14233
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
biomarker, cellular mechanism, eEF2, LRRK2, neurodegeneration, Parkinson's disease
in
FASEB Journal
volume
34
issue
11
pages
17 pages
publisher
Wiley
external identifiers
  • pmid:32926469
  • scopus:85090978275
ISSN
0892-6638
DOI
10.1096/fj.202001046R
language
English
LU publication?
yes
id
d1c532e6-a29d-4d4f-a7ad-cfed4b5f3690
date added to LUP
2020-10-20 11:12:23
date last changed
2024-05-01 17:30:28
@article{d1c532e6-a29d-4d4f-a7ad-cfed4b5f3690,
  abstract     = {{<p>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.</p>}},
  author       = {{Deshpande, Prasannakumar and Flinkman, Dani and Hong, Ye and Goltseva, Elena and Siino, Valentina and Sun, Lihua and Peltonen, Sirkku and Elo, Laura L. and Kaasinen, Valtteri and James, Peter and Coffey, Eleanor T.}},
  issn         = {{0892-6638}},
  keywords     = {{biomarker; cellular mechanism; eEF2; LRRK2; neurodegeneration; Parkinson's disease}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{14217--14233}},
  publisher    = {{Wiley}},
  series       = {{FASEB Journal}},
  title        = {{Protein synthesis is suppressed in sporadic and familial Parkinson’s disease by LRRK2}},
  url          = {{http://dx.doi.org/10.1096/fj.202001046R}},
  doi          = {{10.1096/fj.202001046R}},
  volume       = {{34}},
  year         = {{2020}},
}