West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM.
Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.
Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16842-7.
PubMed.
The most important new result, of which there are several, in this well-written paper from the Dawson laboratory is that the G2019S mutation is gain-of-function for kinase activity. After it was first identified, dardarin was recognized to have a kinase domain (Paisan-Ruiz et al., 2004; Zimprich et al., 2004). It was suggested that mutations might increase kinase activity (Albrecht, 2005; Toft et al., 2005), especially G2019S, which alters a critical residue in the activation loop. West et al. now show that this is the case, leading to the idea that understanding which target(s) are important for dardarin kinase activity will be useful in developing new strategies to understand the molecular etiology of Parkinson disease. The authors also show evidence that an additional mutation, R1441C in the RAS domain N-terminal to G2019S, also increases kinase activity. One target that is useful as a measure of phosphorylation activity in vitro is dardarin itself, but whether this autophosphorylation activity is important in vivo is unclear. Recently, the same mutations in LRRK1 have been shown to slightly decrease kinase activity in very similar assays (Korr, Toschi et al., 2005). Why the two proteins are so variable is unclear, but it is intriguing to think that only LRRK2 mutations have been found in PD patients and perhaps the two kinases are very different in their regulation. Another interesting observation is that dardarin is associated with the mitochondrial membrane in transfected cells. Given the recent excitement about other kinases linked to PD (PINK1) and the involvement of this protein in mitochondrial function, it will be important to see if dardarin mutations lead to mitochondrial damage and whether this represents an important pathway leading to cell loss, or represents one of many targets in the cell.
References:
Albrecht M.
LRRK2 mutations and Parkinsonism.
Lancet. 2005 Apr 2-8;365(9466):1230.
PubMed.
Korr D, Toschi L, Donner P, Pohlenz HD, Kreft B, Weiss B.
LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain.
Cell Signal. 2006 Jun;18(6):910-20.
PubMed.
Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, López de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Martí-Massó JF, Pérez-Tur J, Wood NW, Singleton AB.
Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease.
Neuron. 2004 Nov 18;44(4)
PubMed.
Toft M, Mata IF, Kachergus JM, Ross OA, Farrer MJ.
LRRK2 mutations and Parkinsonism.
Lancet. 2005 Apr 2-8;365(9466):1229-30.
PubMed.
West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM.
Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.
Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16842-7.
PubMed.
Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Müller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T.
Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.
Neuron. 2004 Nov 18;44(4):601-7.
PubMed.
Comments
National Institute on Aging
The most important new result, of which there are several, in this well-written paper from the Dawson laboratory is that the G2019S mutation is gain-of-function for kinase activity. After it was first identified, dardarin was recognized to have a kinase domain (Paisan-Ruiz et al., 2004; Zimprich et al., 2004). It was suggested that mutations might increase kinase activity (Albrecht, 2005; Toft et al., 2005), especially G2019S, which alters a critical residue in the activation loop. West et al. now show that this is the case, leading to the idea that understanding which target(s) are important for dardarin kinase activity will be useful in developing new strategies to understand the molecular etiology of Parkinson disease. The authors also show evidence that an additional mutation, R1441C in the RAS domain N-terminal to G2019S, also increases kinase activity. One target that is useful as a measure of phosphorylation activity in vitro is dardarin itself, but whether this autophosphorylation activity is important in vivo is unclear. Recently, the same mutations in LRRK1 have been shown to slightly decrease kinase activity in very similar assays (Korr, Toschi et al., 2005). Why the two proteins are so variable is unclear, but it is intriguing to think that only LRRK2 mutations have been found in PD patients and perhaps the two kinases are very different in their regulation. Another interesting observation is that dardarin is associated with the mitochondrial membrane in transfected cells. Given the recent excitement about other kinases linked to PD (PINK1) and the involvement of this protein in mitochondrial function, it will be important to see if dardarin mutations lead to mitochondrial damage and whether this represents an important pathway leading to cell loss, or represents one of many targets in the cell.
References:
Albrecht M. LRRK2 mutations and Parkinsonism. Lancet. 2005 Apr 2-8;365(9466):1230. PubMed.
Korr D, Toschi L, Donner P, Pohlenz HD, Kreft B, Weiss B. LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain. Cell Signal. 2006 Jun;18(6):910-20. PubMed.
Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, López de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Martí-Massó JF, Pérez-Tur J, Wood NW, Singleton AB. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron. 2004 Nov 18;44(4) PubMed.
Toft M, Mata IF, Kachergus JM, Ross OA, Farrer MJ. LRRK2 mutations and Parkinsonism. Lancet. 2005 Apr 2-8;365(9466):1229-30. PubMed.
West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16842-7. PubMed.
Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Müller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004 Nov 18;44(4):601-7. PubMed.
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