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Ten years and counting: moving leucine-rich repeat kinase 2 inhibitors to the clinic.

West AB - Mov. Disord. (2014)

Bottom Line: The burden that Parkinson's disease (PD) exacts on the population continues to increase year after year.The leucine-rich repeat kinase 2 (LRRK2) gene was identified in PD genetic studies and offers new hope for novel therapeutic approaches.The evidence linking LRRK2 kinase activity to PD susceptibility is presented, as well as seminal discoveries relevant to the prosecution of LRRK2 kinase inhibition.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

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Selected variants and features in LRRK2 useful for the development of LRRK2-targeting therapies. Arrows reflect approximate position relative to conserved LRRK2 domains. (A) Pathogenic variants, proven by familial segregation, that cause late-onset PD. (B) Variants >1% frequency that are protective or disease-associated, * are variants in Asian populations. R1398H may be the functional variant in a protective haplotype with N551K. (C) Sensitive and specific commercial monoclonal Abs that can detect human and rodent LRRK2. Positions of binding are shown. (D) LRRK2 autophosphorylation sites proven with phospho-specific Abs. (E) Phosphorylation sites on the LRRK2 protein that are not autophosphorylation sites and do not measure LRRK2 activity, but effectively track LRRK2 kinase inhibition, and binding to 14-3-3 proteins. (F) Epitope tags and fluorescent proteins that can be appended to the N- or C-terminus of LRRK2 that have been shown, in biochemical assays, to retain LRRK2 kinase and/or GTPase activity. FLAG (acidic) and bulky proteins such as eGFP have not been compatible with active LRRK2 when attached to the C-terminus. $eGFP, and many other fluorescent proteins, have been appended successfully to the N-terminus. Abbreviations for the LRRK2 protein domains include “LRRK2-repeats” that encode armadillo-like and ankryin-like repeats, “LRR” that is leucine-rich repeats, “ROC” that is ras-of-complex (i.e., GTPase), “COR” that is c-terminal of ras-of-complex, “kinase” that is the kinase domain, and “WD-40” that is WD-40-like repeats. eGFP, enhanced green fluorescent protein. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]
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fig02: Selected variants and features in LRRK2 useful for the development of LRRK2-targeting therapies. Arrows reflect approximate position relative to conserved LRRK2 domains. (A) Pathogenic variants, proven by familial segregation, that cause late-onset PD. (B) Variants >1% frequency that are protective or disease-associated, * are variants in Asian populations. R1398H may be the functional variant in a protective haplotype with N551K. (C) Sensitive and specific commercial monoclonal Abs that can detect human and rodent LRRK2. Positions of binding are shown. (D) LRRK2 autophosphorylation sites proven with phospho-specific Abs. (E) Phosphorylation sites on the LRRK2 protein that are not autophosphorylation sites and do not measure LRRK2 activity, but effectively track LRRK2 kinase inhibition, and binding to 14-3-3 proteins. (F) Epitope tags and fluorescent proteins that can be appended to the N- or C-terminus of LRRK2 that have been shown, in biochemical assays, to retain LRRK2 kinase and/or GTPase activity. FLAG (acidic) and bulky proteins such as eGFP have not been compatible with active LRRK2 when attached to the C-terminus. $eGFP, and many other fluorescent proteins, have been appended successfully to the N-terminus. Abbreviations for the LRRK2 protein domains include “LRRK2-repeats” that encode armadillo-like and ankryin-like repeats, “LRR” that is leucine-rich repeats, “ROC” that is ras-of-complex (i.e., GTPase), “COR” that is c-terminal of ras-of-complex, “kinase” that is the kinase domain, and “WD-40” that is WD-40-like repeats. eGFP, enhanced green fluorescent protein. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Mentions: There are dozens of common nonsynonymous variants scattered throughout the LRRK2 gene in various populations and individuals (http://www.uniprot.org/uniprot/Q5S007) and, possibly, hundreds of rare or idiosyncratic variants. Only a minority of these variants are linked to PD. As yet, there is no biochemical assay, no definitive molecular biology test, to conclusively demonstrate the pathogenicity of a particular variant. Pathogenic mutations in LRRK2 (listed in Fig. 2A) are identified solely by their ability to segregate with disease in families. Idiosyncratic variants, no matter their identity or biochemical effects, cannot be interpreted as pathogenic without strong familial data that generally rely on DNA analysis from more than 5 affected subjects and at least as many unaffected subjects.


Ten years and counting: moving leucine-rich repeat kinase 2 inhibitors to the clinic.

West AB - Mov. Disord. (2014)

Selected variants and features in LRRK2 useful for the development of LRRK2-targeting therapies. Arrows reflect approximate position relative to conserved LRRK2 domains. (A) Pathogenic variants, proven by familial segregation, that cause late-onset PD. (B) Variants >1% frequency that are protective or disease-associated, * are variants in Asian populations. R1398H may be the functional variant in a protective haplotype with N551K. (C) Sensitive and specific commercial monoclonal Abs that can detect human and rodent LRRK2. Positions of binding are shown. (D) LRRK2 autophosphorylation sites proven with phospho-specific Abs. (E) Phosphorylation sites on the LRRK2 protein that are not autophosphorylation sites and do not measure LRRK2 activity, but effectively track LRRK2 kinase inhibition, and binding to 14-3-3 proteins. (F) Epitope tags and fluorescent proteins that can be appended to the N- or C-terminus of LRRK2 that have been shown, in biochemical assays, to retain LRRK2 kinase and/or GTPase activity. FLAG (acidic) and bulky proteins such as eGFP have not been compatible with active LRRK2 when attached to the C-terminus. $eGFP, and many other fluorescent proteins, have been appended successfully to the N-terminus. Abbreviations for the LRRK2 protein domains include “LRRK2-repeats” that encode armadillo-like and ankryin-like repeats, “LRR” that is leucine-rich repeats, “ROC” that is ras-of-complex (i.e., GTPase), “COR” that is c-terminal of ras-of-complex, “kinase” that is the kinase domain, and “WD-40” that is WD-40-like repeats. eGFP, enhanced green fluorescent protein. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig02: Selected variants and features in LRRK2 useful for the development of LRRK2-targeting therapies. Arrows reflect approximate position relative to conserved LRRK2 domains. (A) Pathogenic variants, proven by familial segregation, that cause late-onset PD. (B) Variants >1% frequency that are protective or disease-associated, * are variants in Asian populations. R1398H may be the functional variant in a protective haplotype with N551K. (C) Sensitive and specific commercial monoclonal Abs that can detect human and rodent LRRK2. Positions of binding are shown. (D) LRRK2 autophosphorylation sites proven with phospho-specific Abs. (E) Phosphorylation sites on the LRRK2 protein that are not autophosphorylation sites and do not measure LRRK2 activity, but effectively track LRRK2 kinase inhibition, and binding to 14-3-3 proteins. (F) Epitope tags and fluorescent proteins that can be appended to the N- or C-terminus of LRRK2 that have been shown, in biochemical assays, to retain LRRK2 kinase and/or GTPase activity. FLAG (acidic) and bulky proteins such as eGFP have not been compatible with active LRRK2 when attached to the C-terminus. $eGFP, and many other fluorescent proteins, have been appended successfully to the N-terminus. Abbreviations for the LRRK2 protein domains include “LRRK2-repeats” that encode armadillo-like and ankryin-like repeats, “LRR” that is leucine-rich repeats, “ROC” that is ras-of-complex (i.e., GTPase), “COR” that is c-terminal of ras-of-complex, “kinase” that is the kinase domain, and “WD-40” that is WD-40-like repeats. eGFP, enhanced green fluorescent protein. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]
Mentions: There are dozens of common nonsynonymous variants scattered throughout the LRRK2 gene in various populations and individuals (http://www.uniprot.org/uniprot/Q5S007) and, possibly, hundreds of rare or idiosyncratic variants. Only a minority of these variants are linked to PD. As yet, there is no biochemical assay, no definitive molecular biology test, to conclusively demonstrate the pathogenicity of a particular variant. Pathogenic mutations in LRRK2 (listed in Fig. 2A) are identified solely by their ability to segregate with disease in families. Idiosyncratic variants, no matter their identity or biochemical effects, cannot be interpreted as pathogenic without strong familial data that generally rely on DNA analysis from more than 5 affected subjects and at least as many unaffected subjects.

Bottom Line: The burden that Parkinson's disease (PD) exacts on the population continues to increase year after year.The leucine-rich repeat kinase 2 (LRRK2) gene was identified in PD genetic studies and offers new hope for novel therapeutic approaches.The evidence linking LRRK2 kinase activity to PD susceptibility is presented, as well as seminal discoveries relevant to the prosecution of LRRK2 kinase inhibition.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Show MeSH
Related in: MedlinePlus