Inhibitors of USP30 and methods of using inhibitors of USP30 are provided. In some embodiments, methods of treating conditions involving mitochondrial defects are provided.

Provided herein are fusion protein comprising: an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof; and a targeting domain comprising a moiety that specifically binds a cytosolic protein. Also provided herein are methods of using the fusion proteins to treat a disease, including genetic diseases.

Provided herein are fusion protein comprising: an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof; and a targeting domain comprising a moiety that specifically binds a mitochondrial protein. Also provided herein are methods of using the fusion proteins to treat a disease, including genetic diseases.

Provided herein are fusion protein comprising: an effector domain comprising a catalytic domain of a deubiquitinase, or a functional fragment or functional variant thereof; and a targeting domain comprising a moiety that specifically binds a nuclear protein. Also provided herein are methods of using the fusion proteins to treat a disease, including genetic diseases.

Disclosed are methods for modulating splicing of Ataxin 3 mRNA in an animal with modified oligonucleotides. Such compounds and methods are useful to treat, prevent, or ameliorate spinocerebellar ataxia type 3 (SCA3) in an individual in need thereof.

The present invention identifies biomarkers that are diagnostic of nerve cell injury and/or neuronal disorders. Detection of different biomarkers of the invention are also diagnostic of the degree of severity of nerve injury, the cell(s) involved in the injury, and the subcellular localization of the injury.

The present invention provides compositions comprising chimeric polypeptides that bind to free ubiquitin proteins or free ubiquitin-like proteins with high affinity, as well as chimeric polypeptides that bind to both free and conjugated ubiquitin proteins or free and conjugated ubiquitin-like proteins, and methods of using the chimeric polypeptides to determine the amount of free or total ubiquitin or free or total ubiquitin-like proteins in various types of samples.

The present disclosure relates to methods of treating osteoarthritis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a USP16 inhibitor.

USP14 is a biomarker for recurrent disease and inhibition of USP14 is of therapeutic benefit for women with endometrial or ovarian cancer.

The present invention relates to an inhibitor of ubiquitin-specific peptidase 22 (Usp22 inhibitor) for use in activation of an immune response in a subject and to a kit comprising said Usp22 inhibitor. The present invention further relates to methods for identifying a subject susceptible to treatment of disease by administration of a Usp22 inhibitor and for identifying a compound for activation of an immune response in a subject, as well as to a medicament for treating and/or preventing cancer or an infection comprising (i) a Usp22 inhibitor and (ii) a pharmaceutically acceptable carrier.