Abstract

Our main aim in this project is to understand how mutations across many different domains of LRRK2 cause dominantly inherited Parkinsons disease. We have been particularly looking for shared effects of multiple mutations that are found in many different functional domains of the molecule. In the current period, we have followed up on our previous observations that LRRK2 interacts with two proteins at the trans-Golgi network (TGN), Rab7L1 and GAK. Interestingly, these two proteins are in loci for risk of sporadic Parkinson's disease. We have shown that all mutations in LRRK2 promote the retention of LRRK2 at the TGN. Ongoing work is aimed at understanding the mechanistic basis of this observation. We have several candidate genes that can block or promote LRRK2-Rab7L1 complexes at the TGN and are particularly interested in whether we can establish that the same events occur at the endogenous level, which has motivated us to generate induced pluripotent stem cells (IPSC) carrying LRRK2 mutations.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000948-08
Application #
9147388
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2015
Total Cost
Indirect Cost

  Institution

Name
Aging
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Blauwendraat, Cornelis; Reed, Xylena; Kia, Demis A et al. (2018) Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease. JAMA Neurol :
Kluss, Jillian H; Conti, Melissa M; Kaganovich, Alice et al. (2018) Detection of endogenous S1292 LRRK2 autophosphorylation in mouse tissue as a readout for kinase activity. NPJ Parkinsons Dis 4:13
Mamais, Adamantios; Manzoni, Claudia; Nazish, Iqra et al. (2018) Analysis of macroautophagy related proteins in G2019S LRRK2 Parkinson's disease brains with Lewy Body pathology. Brain Res :
Price, Alice; Manzoni, Claudia; Cookson, Mark R et al. (2018) The LRRK2 signalling system. Cell Tissue Res 373:39-50
Madero-Pérez, Jesús; Fdez, Elena; Fernández, Belén et al. (2018) Parkinson disease-associated mutations in LRRK2 cause centrosomal defects via Rab8a phosphorylation. Mol Neurodegener 13:3
Rudenko, Iakov N; Kaganovich, Alice; Langston, Rebekah G et al. (2017) The G2385R risk factor for Parkinson's disease enhances CHIP-dependent intracellular degradation of LRRK2. Biochem J 474:1547-1558
Civiero, Laura; Cogo, Susanna; Kiekens, Anneleen et al. (2017) PAK6 Phosphorylates 14-3-3? to Regulate Steady State Phosphorylation of LRRK2. Front Mol Neurosci 10:417
Robak, Laurie A; Jansen, Iris E; van Rooij, Jeroen et al. (2017) Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease. Brain 140:3191-3203
Liu, Weiwei; Liu, Xia'nan; Li, Yu et al. (2017) LRRK2 promotes the activation of NLRC4 inflammasome during Salmonella Typhimurium infection. J Exp Med 214:3051-3066
Beilina, Alexandra; Cookson, Mark R (2016) Genes associated with Parkinson's disease: regulation of autophagy and beyond. J Neurochem 139 Suppl 1:91-107

Showing the most recent 10 out of 34 publications