Use of Sumoylation Inhibitors for the Treatment of Neurodegenerative Disease
AssigneeCaritas St. Elizabeth Medical Center of Boston, Inc.
InventorsJin Xu, Nan Zhong
Life of this patent
Estimating the term…
Abstract
The invention generally provides screening methods for the identification of therapeutic compounds useful for the treatment of a neurodegenerative disease, and related prophylactic and therapeutic compositions and methods.
Claims28
A method for identifying a compound useful for the treatment of a neurodegenerative disease, the method comprising:
- (a) contacting a cell with a candidate compound;
- and
- (b) identifying a decrease in sumoylation of a sumoylation substrate in the cell, wherein a compound that decreases sumoylation relative to a reference is a compound that treats a neurodegenerative disease.
4-11. (canceled)
A method for identifying a compound that increases tyrosine hydroxylase expression, the method comprising:
- (a) contacting a cell with a compound;
- and
- (b) identifying a decrease in a sumoylated polypeptide in the cell, wherein a compound that decreases the amount of sumoylated polypeptide relative to a reference is a compound that increases tyrosine hydroxylase expression.
A method for reducing apoptosis, the method comprising:
- (a) contacting a cell at risk of apoptosis with a compound;
- and
- (b) identifying a decrease in a sumoylated polypeptide in the cell, wherein a compound that decreases the amount of sumoylated polypeptide relative to a reference is a compound that reduces apoptosis.
A method for identifying a compound useful for the treatment of a neurodegenerative disease, the method comprising:
- (a) contacting a PSF-expressing cell with a compound;
- and
- (b) identifying a decrease in sumoylated PSF in the cell, wherein a compound that decreases the amount of sumoylated PSF relative to a reference is a compound that treats a neurodegenerative disease.
15-20. (canceled)
A method for identifying a compound that increases tyrosine hydroxylase expression or decreases apoptosis, the method comprising:
- (a) contacting at least a fragment of a PSF polypeptide comprising a sumoylation consensus sequence with a compound under conditions that permit binding;
- and
- (b) detecting binding of the compound to the consensus sequence, wherein a compound that specifically binds the PSF polypeptide increases tyrosine hydroxylase expression or decreases apoptosis.
23-31. (canceled)
A method of identifying a compound that modulates sumoylation, the method comprising:
- (a) contacting a cell expressing a sumoylation-responsive promoter operably linked to a detectable reporter with a candidate compound;
- and
- (b) detecting an alteration in the expression level of the detectable reporter, thereby identifying the compound as modulating sumoylation.
33-39. (canceled)
A method of identifying a compound that treats Parkinson's disease, the method comprising:
- (a) contacting a cell expressing a tyrosine hydroxylase promoter operably linked to a detectable reporter with a candidate compound;
- and
- (b) detecting an alteration in the expression level of the detectable reporter, thereby identifying the compound as modulating sumoylation.
A method for identifying a compound that reduces PSF sumoylation, the method comprising:
- (a) contacting a PSF polypeptide comprising a sumoylation consensus sequence with a compound under conditions that permit SUMO ligation;
- and
- (b) detecting a decrease in PSF sumoylation in the presence of the compound relative to a control condition.
42-43. (canceled)
A method for identifying a compound that increases cleavage of SUMO from a sumoylated polypeptide, the method comprising:
- (a) contacting at least a fragment of a sumoylated polypeptide with a compound under conditions that permit cleavage of a SUMO moiety;
- (b) detecting a decrease in the level of sumoylation in the presence of the compound relative to a reference.
45-49. (canceled)
A method for preventing or ameliorating a neurodegenerative disease selected from the group consisting of Parkinson's disease, Huntington's Disease, Kennedy's Disease, and spinocerebellar ataxia in a subject in need thereof, the method comprising administering to the subject a compound that decreases sumoylation.
51-52. (canceled)
A method for preventing or ameliorating Parkinson's Disease in a subject, the method comprising administering to the subject an effective amount of a histone deacetylase inhibitor that increases tyrosine hydroxylase expression.
A method for preventing or ameliorating Parkinson's Disease in a subject, the method comprising administering to the subject an effective amount of a compound that decreases PSF sumoylation.
56-63. (canceled)
A kit for the treatment or prevention of a neurodegenerative disease, the kit comprising a compound that decreases sumoylation.
A kit for the treatment or prevention of a neurodegenerative disease, the kit comprising a compound that increases tyrosine hydroxylase expression.
A pharmaceutical composition comprising a compound that increases tyrosine hydroxylase selected from the group consisting of sodium butyrate, trichostatin A, and SAHA.
A packaged pharmaceutical comprising:
- (a) an effective amount of an agent that reduces sumoylation of a sumoylation substrate;
- and
- (b) instructions for using the agent to treat a neurodegenerative disease.
Dependencies are inferred from the claim text.