Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease?

BMC Medicine
Iakov N RudenkoMark R Cookson

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial Parkinson's disease (PD). Variation around the LRRK2 locus also contributes to the risk of sporadic PD. The LRRK2 protein contains a central catalytic region, and pathogenic mutations cluster in the Ras of complex protein C terminus of Ras of complex protein (mutations N1437H, R1441G/C and Y1699C) and kinase (G2019S and I2020T) domains. Much attention has been focused on the kinase domain, because kinase-dead versions of mutant LRRK2 are less toxic than kinase-active versions of the same proteins. Furthermore, kinase inhibitors may be able to mimic this effect in mouse models, although the currently tested inhibitors are not completely specific. In this review, we discuss the recent progress in the development of specific LRRK2 kinase inhibitors. We also discuss non-kinase-based therapeutic strategies for LRRK2-associated PD as it is possible that different approaches may be needed for different mutations.

References

Nov 16, 2004·Neuron·Coro Paisán-RuízAndrew B Singleton
May 10, 2005·Annals of Neurology·Manabu FunayamaFumiya Obata
Nov 5, 2005·Proceedings of the National Academy of Sciences of the United States of America·Andrew B WestTed M Dawson
Dec 31, 2005·Proteins·R A BrogliaG Tiana
Jun 6, 2006·Neurobiology of Disease·Elisa GreggioMark R Cookson
Sep 19, 2006·Nature Neuroscience·Wanli W SmithChristopher A Ross
Nov 23, 2006·Neuron·David MacLeodAsa Abeliovich
Apr 6, 2007·Human Molecular Genetics·Ciro IaccarinoPaolo Barone
Apr 20, 2007·Biochemical and Biophysical Research Communications·Patrick A LewisMark R Cookson
Oct 20, 2007·Journal of Neurochemistry·Qiang LiXing-Zhen Chen
Jan 10, 2008·Journal of Neurochemistry·Edward D PloweyCharleen T Chu
Jan 17, 2008·European Journal of Human Genetics : EJHG·Karen NuytemansChristine van Broeckhoven
May 20, 2008·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·J C MöllerW H Oertel
Jun 10, 2008·Lancet Neurology·Daniel G HealyUNKNOWN International LRRK2 Consortium
Jul 2, 2008·Parkinsonism & Related Disorders·Z K WszolekR F Pfeiffer
Sep 23, 2008·Parkinsonism & Related Disorders·Kazuko HasegawaSaburo Yagishita
Nov 5, 2008·Parkinsonism & Related Disorders·Ignacio F MataCyrus P Zabetian
Nov 26, 2008·Biochemical and Biophysical Research Communications·Jason P Covy, Benoit I Giasson
Dec 17, 2008·The FEBS Journal·Vasanti S AnandSteven P Braithwaite
Mar 3, 2009·The Journal of Biological Chemistry·Julia SämannEnrico Schmidt
May 9, 2009·Nature Reviews. Molecular Cell Biology·Raphael GasperAlfred Wittinghofer
Jun 16, 2009·Lancet·Andrew J LeesTamas Revesz
Aug 18, 2009·Nature Neuroscience·Luke S TainAlexander J Whitworth
Sep 29, 2009·Biochimica Et Biophysica Acta·Yongchao LiJunpeng Deng
Nov 17, 2009·Nature Genetics·Javier Simón-SánchezThomas Gasser
Dec 31, 2009·PloS One·Nathan D JorgensenWilliam T Dauer
Jan 30, 2010·Parkinsonism & Related Disorders·Kristoffer Haugarvoll, Zbigniew K Wszolek
May 1, 2010·Neurotoxicology·Jeffery M VanceDonato A Di Monte
May 12, 2010·Proceedings of the National Academy of Sciences of the United States of America·Youren TongJie Shen
Jul 30, 2010·Movement Disorders : Official Journal of the Movement Disorder Society·Jan O AaslyMatthew J Farrer

❮ Previous
Next ❯

Citations

Oct 19, 2012·Nature·Guang-Hui LiuJuan Carlos Izpisua Belmonte
Aug 8, 2013·Nature Medicine·Ralph A Nixon
Nov 30, 2012·Journal of Neuroinflammation·Daniel F MarkerHarris A Gelbard
Sep 20, 2012·Biochemical Society Transactions·Patrick A Lewis, Dario R Alessi
Sep 20, 2012·Biochemical Society Transactions·Jean-Marc Taymans
Sep 20, 2012·Biochemical Society Transactions·Yulan XiongTed M Dawson
Sep 20, 2012·Biochemical Society Transactions·Patricia Gómez-SuagaSabine Hilfiker
Nov 12, 2013·Expert Opinion on Therapeutic Targets·Sharon L ChanEng-King Tan
May 27, 2015·Current Neurology and Neuroscience Reports·Mark R Cookson
Sep 13, 2013·Small GTPases·Elpida Tsika, Darren J Moore
Jul 11, 2014·Frontiers in Molecular Neuroscience·Nicolas DzamkoGlenda M Halliday
Dec 20, 2012·Parkinson's Disease·Patricia Gómez-SuagaSabine Hilfiker
Dec 13, 2016·CNS Neuroscience & Therapeutics·Qi QinHui Zhang
Jan 8, 2016·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·A Raquel Esteves, Sandra M Cardoso
Aug 20, 2017·The Journal of Experimental Medicine·Weiwei LiuZizhen Kang
Aug 2, 2018·The EMBO Journal·Sandra-Fausia SoukupPatrik Verstreken
Jun 25, 2014·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Iakov N Rudenko, Mark R Cookson
Mar 19, 2016·Oncotarget·Sandeep Vasant More, Dong-Kug Choi
Jul 6, 2020·Journal of Neuroscience Research·Jinelle M Wint, Howard I Sirotkin
Nov 27, 2019·Biochemical Society Transactions·Rebecca L Wallings, Malú G Tansey
Apr 23, 2015·The FEBS Journal·Rebecca WallingsRina Bandopadhyay
Jan 26, 2020·Nature Reviews. Neurology·Eduardo TolosaOlivier Rascol
Dec 20, 2018·International Journal of Molecular Sciences·Jingling Liao, Quyen Q Hoang
Oct 21, 2020·Biochemical Society Transactions·Ahmed SolimanArjan Kortholt
Jan 21, 2021·Cells·Joanne TohEng King Tan
Jul 10, 2021·Frontiers in Neurology·Albert Frank MagnusenManoj Kumar Pandey
May 18, 2012·Journal of Medicinal Chemistry·Huifen ChenDaniel J Burdick
Jan 10, 2013·ACS Medicinal Chemistry Letters·Bryan K ChanZachary K Sweeney

❮ Previous
Next ❯

Methods Mentioned

BETA
GTPase
protein folding
transgenic

Software Mentioned

ROC

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.