Abstract: The present invention relates to a biomarker for Parkinson's disease. The biomarker and products associated with the biomarker may be used to assist diagnosis or to assess onset and/or development of Parkinson's disease. The invention also relates to use of the biomarker in clinical screening, assessment of prognosis, evaluation of drug treatments, drug screening or drug development in the field of Parkinson's disease and Parkinson's disease related disorders.

Abstract: A method for assessing the effect of a test compound on LRRK2 in a cell-based system, the method comprising the steps of a) assessing the effect of exposing the cell-based system comprising LRRK2 to the test compound on the phosphorylation state of Ser910 and/or Ser935 of the LRRK2; and/or b) assessing the effect of exposing the cell-based system comprising LRRK2 to the test compound on the binding of the LRRK2 to a 14-3-3 polypeptide. The method may comprise or further comprise the step of assessing the effect of exposing the cell-based system comprising LRRK2 to the test compound on the subcellular location of LRRK2. The method is considered to be useful in assessing the effect of putative LRRK2 inhibitors in cell based systems, including in vivo systems.

Abstract: A method for identifying a compound expected to be useful in modulating, for example inhibiting, LRRK2 protein kinase activity, the method comprising the steps of (1) determining whether a test compound modulates, for example inhibits, the protein kinase activity of a LRRK2 polypeptide on a substrate polypeptide and (2) selecting a compound which modulates, for example inhibits, the said LRRK2 polypeptide protein kinase activity, wherein the substrate polypeptide comprises the sequence (W/F/R/K)(W/F/R/K)(R/K)(F/W/H/R)(Y/W/R)(S/T)(L/V/I) (R/K)(R/K)(A/Y) or (W/R)(X)(X)(F/Y/H/T)(Y/W/R)(T)(X)(R/T)(R)(X), where X represents any amino acid. Such a compound may be useful in treating Parkinson's Disease or Parkinsonism. The substrate polypeptide may consist or comprise the sequence RLGWWRFYTLRRARQGNTKQ.

Abstract: The invention concerns RAC-PK and fragments thereof, as well as activators and inhibitors of RAC-PK for use as medicaments, particularly in the treatment of diseases concerned with abnormalities in processes modulated by insulin, such as cellular proliferation, insulin deficiency and/or excess blood sugar levels. Moreover, the invention provides RAC-PK for use in screening potential mimics or modulators thereof. A method for screening for agents capable of affecting the activity of GSK3 is also disclosed. The invention further provides a screening kit comprising the RAC-PK as an active principle, and a method for screening compounds which are candidate mimics or modulators of RAC-PK activity comprising detecting specific interactions between the candidate compounds and RAC-PK. There is also provided a process for activating RAC-PK comprising treatment thereof with a phosphatase inhibitor.

Abstract: A method for assessing the effect of a test compound on LRRK2 in a cell-based system, the method comprising the steps of a) assessing the effect of exposing the cell-based system comprising LRRK2 to the test compound on the phosphorylation state of Ser910 and/or Ser935 of the LRRK2; and/or b) assessing the effect of exposing the cell-based system comprising LRRK2 to the test compound on the binding of the LRRK2 to a 14-3-3 polypeptide. The method is considered to be useful in assessing the effect of putative LRRK2 inhibitors in cell based systems, including in vivo systems.

Abstract: A method for assessing the effect of a test compound on LRRK2 in a cell-based system, the method comprising the steps of a) assessing the effect of exposing the cell-based system comprising LRRK2 to the test compound on the phosphorylation state of Ser910 and/or Ser935 of the LRRK2; and/or b) assessing the effect of exposing the cell-based system comprising LRRK2 to the test compound on the binding of the LRRK2 to a 14-3-3 polypeptide. The method may comprise or further comprise the step of assessing the effect of exposing the cell-based system comprising LRRK2 to the test compound on the subcellular location of LRRK2. The method is considered to be useful in assessing the effect of putative LRRK2 inhibitors in cell based systems, including in vivo systems.

Abstract: A method for identifying a compound expected to be useful in modulating a LRRK2 protein kinase activity, the method comprising the steps of (1) determining whether a test compound modulates the protein kinase activity of a LRRK2 polypeptide on a substrate Ezrin/Radixin/moesin (ERM) family polypeptide and (2) selecting a compound which modulates the LRRK2 polypeptide protein kinase activity. Such a compound may be useful in treating Parkinson's Disease or Parkinsonism. A catalytically active fragment of LRRK2 is identified, requiring the GTPase, COR and kinase domains as well as the WD_40-like motif and C-terminal tail.

Abstract: The invention concerns RAC-PK and fragments thereof, as well as activators and inhibitors of RAC-PK for use as medicaments, particularly in the treatment of diseases concerned with abnormalities in processes modulated by insulin, such as cellular proliferation, insulin deficiency and/or excess blood sugar levels. Moreover, the invention provides RAC-PK for use in screening potential mimics or modulators thereof. A method for screening for agents capable of affecting the activity of GSK3 is also disclosed. The invention further provides a screening kit comprising the RAC-PK as an active principle, and a method for screening compounds which are candidate mimics or modulators of RAC-PK activity comprising detecting specific interactions between the candidate compounds and RAC-PK. There is also provided a process for activating RAC-PK comprising treatment thereof with a phosphatase inhibitor.

Abstract: A method for selecting a compound for modulating the activity of phosphoinositide dependent protein kinase 1 (PDKI) is provided. The method may comprise modelling a three dimensional structure of a plurality of molecules in a computer, comparing with the three dimensional structure of the compounds with that of a reference structure such as at least part of a protein kinase catalytic domain of PDK1, and selecting the compound based on a predicted interacting ability of the molecules to the protein kinase catalytic domain. Also a method for selecting a compound for modulating the activity of hydrophobic pocket containing protein kinase is provided. In this method, the reference structures may be one or more of a phosphate binding pocket of PDK1, a hydrophobic pocket of PDK1, and ?C helix or region interacting therewith of PDK1.

Abstract: A method for identifying a compound expected to be useful in modulating, for example inhibiting, LRRK2 protein kinase activity, the method comprising the steps of (1) determining whether a test compound modulates, for example inhibits, the protein kinase activity of a LRRK2 polypeptide on a substrate polypeptide and (2) selecting a compound which modulates, for example inhibits, the said LRRK2 polypeptide protein kinase activity, wherein the substrate polypeptide comprises the sequence (W/F/R/K)(W/F/R/K)(R/K)(F/W/H/R)(Y/W/R)(S/T)(L/V/I) (R/K)(R/K)(A/Y) or (W/R)(X)(X)(F/Y/H/T)(Y/W/R)(T)(X)(R/T)(R)(X), where X represents any amino acid. Such a compound may be useful in treating Parkinson's Disease or Parkinsonism. The substrate polypeptide may consist or comprise the sequence RLGWWRFYTLRRARQGNTKQ.

Abstract: The use of polypeptides capable of binding to PtdIns(3,4)P2, PtdIns3P, PtdIns4P or but not capable of binding to PtdIns(3,4,5)P3, in a screening method for identifying a compound suitable for modulating signalling by PtdIns(3,4)P2, PtdIns3P, PtdIns4P or PtdIns(3,5)P2. The polypeptides preferably comprises a PH (pleckstrin homology) domain which binds specifically to one of PtdIns(3,4)P2, PtdIns3P, PtdIns4P or PtdIns(3,5)P2. The PH domain preferably has at least five of the six residues of a Putative PtdIns(3,4,5)P3 Binding Motif (PPBM).

Abstract: A method for identifying a compound expected to be useful in modulating a LRRK2 protein kinase activity, the method comprising the steps of (1) determining whether a test compound modulates the protein kinase activity of a LRRK2 polypeptide on a substrate Ezrin/Radixin/moesin (ERM) family polypeptide and (2) selecting a compound which modulates the LRRK2 polypeptide protein kinase activity. Such a compound may be useful in treating Parkinson's Disease or Parkinsonism. A catalytically active fragment of LRRK2 is identified, requiring the GTPase, COR and kinase domains as well as the WD_40-like motif and C-terminal tail.

Abstract: The invention concerns RAC-PK and fragments thereof, as well as activators and inhibitors of RAC-PK for use as medicaments, particularly in the treatment of diseases concerned with abnormalities in processes modulated by insulin, such as cellular proliferation, insulin deficiency and/or excess blood sugar levels. Moreover, the invention provides RAC-PK for use in screening potential mimics or modulators thereof. A method for screening for agents capable of affecting the activity of GSK3 is also disclosed. The invention further provides a screening kit comprising the RAC-PK as an active principle, and a method for screening compounds which are candidate mimics or modulators of RAC-PK activity comprising detecting specific interactions between the candidate compounds and RAC-PK. There is also provided a process for activating RAC-PK comprising treatment thereof with a phosphatase inhibitor.

Abstract: A method of identifying a compound that modulates the protein kinase activity of a protein kinase having a hydrophobic pocket in the position equivalent to the hydrophobic pocket of Protein Kinase A (PKA) that is defined by residues including Lys76, Leu116, Val80 and/or Lys111 of full-length mouse PKA, wherein the ability of the compound to inhibit, promote or mimic the interaction of the said hydrophobic pocket-containing protein kinase with an interacting polypeptide is measured and a compound that inhibits, promotes or mimics the said interaction is selected, wherein the interacting polypeptide interacts with the hydrophobic pocket of the protein kinase and/or comprises the amino acid sequence Phe/Tyr-Xaa-Xaa-Phe/Tyr.

Abstract: The present invention relates to methods of altering the substrate specificity of PDK1, methods of identifying compounds which modulate the activity of PDK1 and methods of using PDK1 having altered substrate specificity.

Abstract: A method for identifying a compound for modulating the cellular activity or location of PTPL1, comprising the step of identifying a compound that modulates the interaction of PTPL1 with TAPP; or which modulates or mimics the interaction of TAPP with Ptdlns(3, 4)P2; or which modulates the cellular location of TAPP. A method of treating a patient with diabetes or in need of inhibition of apoptosis, for example in the treatment of ischaemic disease, wound healing or nerve regeneration, wherein the patient is administered an effective amount of a compound that inhibits the interaction of PtdIns(3, 4)P2 with TAPP or that inhibits the interaction of TAPP with PTPL1.

Abstract: A method for identifying a compound for use in modulating, for example promoting, the activation or phosphorylation of AMPK (AMP-activated protein kinase) or AMPK subfamily member in a cell, the method comprising the steps of (1) determining whether a test compound modulates, for example promotes, the protein kinase activity of LKB1 and (2) selecting a compound which modulates, for example promotes, the protein kinase activity of LKB1. The protein kinase activity may be tested using AMPK or an AMPK subfamily member, or a peptide encompassing the T-loop region of AMPK or an AMPK subfamily member. The LKB1 may be in a preparation or complex with STRAD and/or M025, which has much greater kinase activity than LKB1 in the absence of these accessory proteins. The LKB1, STRAD or M025 may be recombinant. The AMPK subfamily member may be AMPK?1, AMPK?2, NUAK1, NUAK2, BRSK1, BRSK2, SIK, QIK, QSK, MARK1, MARK2, MARK3, MARK4 or MELK.

Abstract: Substantially pure two kinase domain protein kinases comprising the amino acid sequences provided in the description, variants, fusions, fragments, or derivatives thereof useful in screening assays for drugs. Applications thereof in the modulation of CREB, COX2 and IL2 activities.

Abstract: A liquid reactant metal alloy (210) includes at least one chemically active metal for reacting with non-radioactive material in a mixed waste stream being treated. The reactant alloy (210) also includes at least one radiation absorbing metal. Radioactive isotopes in the waste stream alloy with, or disperse in, the chemically active and radiation absorbing metals such that the radiation absorbing metals are able to absorb a significant portion of the radioactive emissions associated with the isotopes. Non-radioactive constituents in the waste material are broken down into harmless and useful constituents, leaving the alloyed radioactive isotopes in the liquid reactant alloy. The reactant alloy may then be cooled to form one or more ingots in which the radioactive isotopes are effectively isolated and surrounded by the radiation absorbing metals. These ingots comprise storage products for the radioactive isotopes.

Abstract: The invention concerns RAC-PK and fragments thereof, as well as activators and inhibitors of RAC-PK for use as medicaments, particularly in the treatment of diseases concerned with abnormalities in processes modulated by insulin, such as cellular proliferation, insulin deficiency and/or excess blood sugar levels. Moreover, the invention provides RAC-PK for use in screening potential mimics or modulators thereof. A method for screening for agents capable of affecting the activity of GSK3 is also disclosed. The invention further provides a screening kit comprising the RAC-PK as an active principle, and a method for screening compounds which are candidate mimics or modulators of RAC-PK activity comprising detecting specific interactions between the candidate compounds and RAC-PK. There is also provided a process for activating RAC-PK comprising treatment thereof with a phosphatase inhibitor.