Methods for the diagnosis and treatment of neurological and neurodegenerative diseases, disorders and associated processes

An in vitro method of identifying an agent that increases alpha-synuclein clearance or decreases alpha-synuclein synthesis in a cell comprising:

• (a) contacting a first cell in a first cell culture media with a labeled amino acid and an agent to determine whether the agent increases alpha-synuclein clearance or decreases alpha-synuclein synthesis, wherein the labeled amino acid incorporates into alpha-synuclein protein during alpha-synuclein synthesis in the first cell, thereby producing labeled and detectable alpha-synuclein in the first cell culture media;
• (b) collecting alpha-synuclein from the first cell culture media;
• (c) determining a first metabolic incorporation of the labeled amino acid into alpha-synuclein in the first cell culture media, wherein determining the first metabolic incorporation comprises measuring the amount of labeled alpha-synuclein and unlabeled alpha-synuclein in an alpha-synuclein polypeptide selected from the group consisting of SEQ ID NOs:
• 4 to SEQ ID NO:
• 13, in the first cell culture media via a stable isotope labeling kinetics (SILK) assay, and providing a first ratio of labeled alpha-synuclein to unlabeled alpha-synuclein polypeptide;
• (d) determining a second metabolic incorporation of the labeled amino acid into alpha-synuclein in a second cell culture media collected from a second cell contacted with the labeled amino acid of (a) and not contacted with the agent, wherein determining the second metabolic incorporation comprises measuring the amount of labeled alpha-synuclein and unlabeled alpha-synuclein in an alpha-synuclein polypeptide selected from the group consisting of SEQ ID NOs:
• 4 to SEQ ID NO:13, in the second cell culture media via the SILK assay, and providing a second ratio of labeled alpha-synuclein to unlabeled alpha-synuclein polypeptide, wherein the first and second cell are obtained from a subject;
• and
• (e) identifying the agent as an agent that increases alpha-synuclein clearance or decreases alpha-synuclein synthesis when the first ratio is less than the second ratio,
• wherein the agent is selected from a small molecule inhibitor, an antibody, a sirtuin 2 inhibitor, a proteosome inhibitor, L-DOPA, a cholesterylester transfer protein (CEPT) inhibitor, a metalloprotease inhibitor, a cholinesterase inhibitor, an NMDA receptor antagonist, a hormone, a neuroprotective agent, or a cell death inhibitor, and
• wherein the first cell and the second cells are neuronal cells from the same subject.