TRANSCRIPTIONAL REPRESSION LEADING TO PARKINSON'S DISEASE

• US 20120122958A1
• Filed: 11/11/2011
• Published: 05/17/2012
• Est. Priority Date: 11/11/2010
• Status: Active Grant

• Current Assignee: Valted, LLC
• Original Assignee: Valted, LLC
• Inventors: Dawson, Ted M., Dawson, Valina L., Ko, Han Seok, Shin, Jooho
• Granted Patent: US 8,603,994 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/531 Stem-loop; Hairpin
• CPC Class Codes: C12N 2320/30 Special therapeutic applications
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: C12Y 603/02019 Ubiquitin-protein ligase (6.3.2.19), i.e. ubiquitin-conjugating enzyme
• CPC Class Codes: G01N 2333/4704 Inhibitors; Supressors
• CPC Class Codes: G01N 2800/2835 Movement disorders, e.g. Parkinson, Huntington, Tourette
• CPC Class Codes: G01N 33/6872 Intracellular protein regulatory factors and their receptors, e.g. including ion channels
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease

Abstract

Parkinson'"'"'s disease is caused by the preferential loss of substantia nigra dopamine neurons. A Parkin Interacting Substrate, PARIS (ZNF746) is identified. The levels of PARIS are regulated by the ubiquitin proteasome system via binding to and ubiquitination by the E3 ubiquitin ligase, parkin. PARIS is a KRAB and zinc finger protein that accumulates in models of parkin inactivation and in human brain Parkinson'"'"'s disease patients. PARIS represses the expression of the transcriptional co-activator, PGC-1α and the PGC-1α target gene, NRF-1 by binding to insulin response sequences in the PGC-1α promoter. Conditional knockout of parkin in adult animals leads to progressive loss of dopamine (DA) neurons that is PARIS dependent. Overexpression of PARIS causes selective loss of DA neurons in the substantia nigra, which is reversed by either parkin or PGC-1α co-expression. The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation.

Claims

1. A method to diagnose Parkinson'"'"'s disease comprising the steps of:

measuring an amount of a component in a sample, wherein the component is selected from the group consisting of Parkin Interacting Substrate, a metabolite of Parkin Interacting Substrate, an mRNA coding for Parkin Interacting Substrate, PGC-1α

, and an mRNA coding for PGC-1α

; and

comparing the amount of the component against a baseline value.

2. The method of claim 1, wherein the sample is selected from the group consisting of urine, blood, cerebra-spinal fluid brain, bodily fluid and tissue.

3. A method of treating Parkinson'"'"'s disease and related disorders comprising;

administering an inhibitor of Parkin Interacting Substrate to a mammal.

4. The method of claim 3, wherein the inhibitor is selected from the group of an shRNA inhibitor and an anti-sense microRNA inhibitor.

5. An isolated polynucleotide comprising a sequence selected from the group consisting of SEQ ID NO:

5 to SEQ ID NO;

136.

6. The isolated polynucleotide of claim 5, wherein the nucleotide is SEQ ID NO. 27.

7. The isolated polynucleotide of claim 5, wherein the nucleotide is SEQ ID NO. 28.

8. A composition comprising the isolated polynucleotide of claim 5.

9. A method of treatment for Parkinson'"'"'s disease and related disorders, comprising administering a pharmaceutically effective amount of the composition of claim 8.

10. A kit comprising the composition of claim 8 and instructions on their use.