Truncated fragments of alpha-synuclein in Lewy body disease
View Patent ↗The application identifies fragments of alpha-synuclein in patients with Lewy Body Disease (LBD) and transgenic animal models thereof. These diseases are characterized by aggregations of alpha-synuclein. The fragments have a truncated C-terminus relative to full-length alpha-synuclein. Some fragments are characterized by a molecular weight of about 12 kDa as determined by SDS gel electrophoresis in tricine buffer and a truncation of at least ten contiguous amino acids from the C-terminus of natural alpha-synuclein. The site of cleavage preferably occurs after residue 117 and before residue 126 of natural alpha-synuclein. The identification of these novel fragments of alpha-synuclein has a number of application in for example, drug discovery, diagnostics, therapeutics, and transgenic animals.
1. A method of screening for an agent having a pharmacological activity useful for treating a Lewy Body Disease (LBD) comprising:
contacting the agent with a fragment of alpha-synuclein, wherein the fragment consists of residues 1-119 or 1-122 of SEQ ID NO:1 or a mutation associated with hereditary Lewy Body Disease;
determining the rate or extent of aggregation of the fragment of alpha-synuclein, wherein a reduction in the rate or extent of aggregation relative to a control lacking the agent indicates the agent has the pharmacological activity.
2. The method of claim 1 , wherein the fragment of alpha-synuclein is SN1-122.
3. The method of claim 2 , wherein the fragment of alpha-synuclein is SN1-119.
4. The method of claim 1 , wherein the fragment of alpha-synuclein bears a mutation associated with a hereditary LBD.
5. The method of claim 4 , wherein the mutation is an A53T mutation.
6. A fragment of alpha-synuclein prepared by peptide synthesis or recombinant expression, wherein the fragment consists of residues 1-119 or 1-122 of SEQ ID NO:1 or a mutation associated with hereditary Lewy Body Disease.
7. The fragment of claim 6 , wherein the fragment of alpha-synuclein bears a mutation associated with a hereditary LBD.
8. The fragment of claim 6 , wherein the fragment of alpha-synuclein is SN 1-119.
9. The fragment of claim 6 , wherein the fragment of alpha-synuclein is SN1-122.
10. The fragment of claim 6 , wherein the fragment is linked to a heterologous polypeptide.
11. The method of claim 7 , wherein the mutation is an A53T mutation.