Abstract: The present disclosure provides novel gene therapy constructs comprising a PARK2 gene or activating variant and methods of administering to treat Parkinson's Disease or symptoms thereof.

Abstract: The present disclosure relates to methods of treating cancer comprising administering Parkin ligase activator or a pharmaceutically acceptable salt thereof to a subject who has a mutant form of a protein in the Rb checkpoint pathway. The Parkin ligase activator includes triazole compounds, such as compounds of formula (I), and pharmaceutically acceptable salts thereof as disclosed herein. R1, R2, R3, M1, M2, M3, L1, L2, and L3 are as defined herein.

Abstract: The present disclosure is directed to asymmetric triazole benzamide compounds of formula (I) and formula (II), pharmaceutical compositions thereof and methods for modulating or activating a Parkin ligase The present disclosure is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase. R1, R2, R3, M1, M2, M3, L1, L2, and L3 are as defined herein.

Abstract: The present disclosure is directed to pyrazolo[1,5-a]pyrimidine compounds of formula (I), pharmaceutical compositions thereof and methods for modulating or activating a Parkin ligase The present disclosure is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase. R21, R22, R23, R24 and R25 are as defined herein.

Abstract: The present disclosure is directed to asymmetric triazole benzamide compounds of formula (I) and formula (II), pharmaceutical compositions thereof and methods for modulating or activating a Parkin ligase The present disclosure is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase. R1, R2, R3, M1, M2, M3, L1, L2, and L3 are as defined herein.

Abstract: The present disclosure is directed to pyrazolo[1,5-a]pyrimidine compounds of formula (I), pharmaceutical compositions thereof and methods for modulating or activating a Parkin ligase The present disclosure is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase. R21, R22, R23, R24 and R25 are as defined herein.

Abstract: The present disclosure is directed to asymmetric triazole benzamide compounds of formula (I) and formula (II), pharmaceutical compositions thereof and methods for modulating or activating a Parkin ligase The present disclosure is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase. R1, R2, R3, M1, M2, M3, L1, L2, and L3 are as defined herein.

Abstract: Described herein are MCAM antagonists, including MCAM antagonist antibodies capable of inhibiting the interaction between MCAM and it ligand, a laminin a4 chain, e.g., an ct4 chain of laminin 41 1. These MCAM antagonists, e.g., anti-MCAM antibodies, may be useful to treat neuroinflammatory conditions, for example, multiple sclerosis and Parkinson's disease, by inhibiting the infiltration of MCAM-expressing cells into the central nervous system (CNS), e.g., extravasation of TH 17 cells into the CNS.

Abstract: The present invention is directed to methods and compositions for activating a Parkin ligase by administering to a subject in need thereof a therapeutically effective amount of a compound that disrupts at least one Parkin ligase zinc finger. The present invention is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase.

Abstract: The present disclosure is directed to triazole benzamide compounds of formula (I) and formula (II), pharmaceutical compositions thereof and methods for modulating or activating a Parkin ligase The present disclosure is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase. R1, R2, R3, M1, M2, M3, L1, L2, and L3 are as defined herein.

Abstract: The present disclosure is directed to triazole benzamide compounds of formula (I) and formula (II), pharmaceutical compositions thereof and methods for modulating or activating a Parkin ligase The present disclosure is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase. R1, R2, R3, M1, M2, M3, L1, L2, and L3 are as defined herein.

Abstract: The present invention is directed to methods and compositions for activating a Parkin ligase by administering to a subject in need thereof a therapeutically effective amount of a compound that disrupts at least one Parkin ligase zinc finger. The present invention is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase.

Abstract: The present disclosure is directed to triazole benzamide compounds of formula (I) and formula (II), pharmaceutical compositions thereof and methods for modulating or activating a Parkin ligase The present disclosure is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase. R1, R2, R3, M1, M2, M3, L1, L2, and L3 are as defined herein.

Abstract: The present invention provides a screen which exploits mechanism-based activity probes that specifically and covalently modify the active site cysteine thiol residue of E3 Ub ligases including, but not limited to the HECT and RBR family. The activity probes are used to screen for activators and inhibitors of E3 Ub ligases, and to interrogate the functional state of E3 Ub ligases in human disease.

Abstract: The present invention is directed to methods and compositions for activating a Parkin ligase by administering to a subject in need thereof a therapeutically effective amount of a compound that disrupts at least one Parkin ligase zinc finger. The present invention is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase.

Abstract: The present invention provides a screen which exploits mechanism-based activity probes that specifically and covalently modify the active site cysteine thiol residue of E3 Ub ligases including, but not limited to the HECT and RBR family. The activity probes are used to screen for activators and inhibitors of E3 Ub ligases, and to interrogate the functional state of E3 Ub ligases in human disease.

Abstract: Described herein are MCAM antagonists, including MCAM antagonist antibodies capable of inhibiting the interaction between MCAM and it ligand, a laminin ?4 chain, e.g., an ?4 chain of laminin 411. These MCAM antagonists, e.g., anti-MCAM antibodies, may be useful to treat neuroinflammatory conditions, for example, multiple sclerosis and Parkinson's disease, by inhibiting the infiltration of MCAM-expressing cells into the central nervous system (CNS), e.g., extravasation of TH17 cells into the CNS.

Abstract: The invention provides methods of screening for agents useful in treating or prophylaxis of synucleinopathic disease, methods of diagnosis or prognosis of the same and methods of treatment and prophylaxis. The invention is based in part on the result that cells with phagocytic activity from subjects with synucleinopathic disease have increased levels of alpha synuclein and reduced phagocytic activity and that these processes can be reversed (i.e., synuclein levels decreased and phagocytic levels increased) by treatment with IL-4 among other agents. The increase in phagocytic activity is readily amenable to detection and provides a basis for a screening assay in which an agent is contacted with phagocytic cells and the effect of the agent on phagocytic activity is detected, which is an indicator that the agent has the ability to reduce alpha synuclein levels.

Abstract: The invention provides transgenic animals having a transgene comprising a genomic human alpha synuclein segment including six exons, five introns and at least one mutation associated with synucleinopathic disease operably linked to a human alpha synuclein promoter. The transgenic animals have characteristics of synucleinopathic disease including elevated levels of alpha synuclein in the brain, formation of intracellular deposits of alpha synuclein that have at least one, and preferably all features of Lewy bodies, formation of alpha-synuclein fragments, or phosphorylated forms of alpha synuclein, loss of neuronal cells, glial cells or oligodentricytes, impairment of motor function and/or impairment of cognitive function.

Abstract: The invention provides in vitro, ex vivo, and in vivo assays for Parkin activity, in which Parkin-mediated ubiquitination of a Sept4 protein is measured. The assays may be used to screen for agents that modulate Parkin protein ligase activity.