Compositions and methods targeting swip-10 and mblac1 for the therapeutic modulation of copper dyshomeostasis

A method to identify agents or manipulations that modulate Cu dyshomeostasis in an Mblac1- or swip-10-dependent manner comprising:

• (i) providing a plurality of Mblac1 or swip-10 KD or KO animals, and a plurality of Mblac1 or swip-10 WT animals;
• (ii) measuring a baseline value for at least one Cu marker for each animal;
• (iii) exposing each animal to at least one test agent or manipulation, wherein each animal provides its own baseline value prior to exposure;
• (iv) at a first post-exposure time point, measuring at least one exposure response value for the at least one Cu marker for each animal;
• (v) optionally, at one or more of a second, third, fourth, fifth and sixth post-exposure time point, measuring an exposure response value for the at least one Cu marker for each animal;
• (vi) averaging the WT exposure response values compared to the WT baseline values, averaging the KO/KD exposure response values compared to the KO/KD baseline values, and then comparing the WT average to the KO or KD average, wherein if the WT average is different relative to the KO or KD average, the at least one test agent or manipulation modulates Cu dyshomeostasis.

A method to identify agents that support Cu-dependent neuronal health in a subject comprising:

• (i) providing a plurality of Mblac1 or swip-10 KD or KO animals, and a plurality of MBLAC1 or swip-10 WT animals;
• (ii) exposing a first portion of the plurality of Mblac1 or swip-10 KD or KO animals and a first portion of the plurality of Mblac1 or swip-10 WT animals to a neural toxin or other neural insult that results in pathology in a Cu-dependent manner, wherein a second portion of the Mblac1 or swip-10 KD or KO animals and a second portion of the Mblac1 or swip-10 WT animals are not exposed to the neural toxin or neural insult as controls;
• (iii) measuring the pathology in each exposed animal;
• (iv) administering a test agent to at least the first portion of the plurality of Mblac1 or swip-10 KD or KO animals and the first portion of the plurality of Mblac1 or swip-10 WT animals;
• (v) measuring the pathology in each animal that was administered the test agent;
• (vi) identifying the test agent as an agent that supports Cu-dependent neuronal health in a subject if the test agent reverses the pathology of an Mblac1 KO.

A method to identify agents or manipulations that modulate Cu dyshomeostasis in an Mblac1- or swip-10-dependent manner comprising:

• (i) providing a first group of cultured cells derived from a plurality of Mblac1 or swip-10 KD or KO animals, and a second group of cultured cells derived from a plurality of Mblac1 or swip-10 WT animals;
• (ii) exposing a first portion of the first group of cultured cells and a first portion of the second group of cultured cells to at least one test agent or manipulation, and exposing a second portion of the first group of cultured cells and a second portion of the second group of cultured cells to a control vehicle;
• (iii) measuring a value for at least one Cu marker in each of the portions and comparing the effects of the at least one test agent or manipulation between the first portion of the first group of cultured cells and the second portion of the second group of cultured cells;
• and
• (iv) identifying the at least one test agent or manipulation as one that modulates Cu dyshomeostasis if at least one of the following is observed:
• the value for the at least one Cu marker from the first portion of the first group of cultured cells is statistically different from the value for the at least one Cu marker from the second portion of the first group of cultured cells;
• the value for the at least one Cu marker from the first portion of the second group of cultured cells is statistically different from the value for the at least one Cu marker from the second portion of the second group of cultured cells;
• and the value for the at least one Cu marker from the first portion of the first group of cultured cells animals is equal or similar to the value for the at least one Cu marker from the first and/or second portions of the second group of cultured cells.

A method to identify agents or manipulations that modulate Cu dyshomeostasis in an Mblac1- or swip-10-dependent manner comprising:

• (i) providing a first group of cultured cells derived from a plurality of Mblac1 or swip-10 KD or KO animals, and a second group of cultured cells derived from a plurality of Mblac1 or swip-10 WT animals;
• (ii) measuring a baseline value for at least one Cu marker in both groups of cultured cells;
• (iii) exposing both groups of cultured cells to at least one test agent or manipulation, wherein each cultured cell provides its own baseline value prior to exposure;
• (iv) at a first post-exposure time point, measuring at least one exposure response value for the at least one Cu marker for both groups of cultured cells;
• (v) optionally, at one or more of a second, third, fourth, fifth and sixth post-exposure time point, measuring an exposure response value for the at least one Cu marker for both groups of cultured cells;
• and
• (vi) averaging the second group of cultured cells' exposure response values compared to the second group of cultured cells' baseline values, averaging the first group of cultured cells' exposure response values compared to the first group of cultured cells' baseline values, and then comparing the second group of cultured cells' average to the first group of cultured cells' average, wherein if the second group of cultured cells' average is different relative to the first group of cultured cells' average, the at least one test agent or manipulation modulates Cu dyshomeostasis.