MID1 inhibitors to delay disease progression in neurodegenerative diseases
Baski, Nahawand (2024-04-16)
MID1 inhibitors to delay disease progression in neurodegenerative diseases
(16.04.2024)
Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
avoin
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2024051732060
https://urn.fi/URN:NBN:fi-fe2024051732060
Tiivistelmä
Neurodegenerative diseases (NDs) are characterized by neuronal damage where nerve cells degenerate and
die. Alzheimer’s and Parkinson’s diseases are the most prevalent and well-known NDs. Current treatments
alleviate the symptoms but are unable to slow the progression of the disease or the destruction of the nerve
cells. Therefore, finding novel therapies that could modify the course of neurodegenerative diseases is
important.
Midline 1 (MID1), a ubiquitin ligase, is a novel potential target for drug development. The protein forms a
complex with protein phosphatase 2A (PP2A) and its subunit α4 and transports them to proteasomes for
degradation. MID1-inhibitors aim to prevent the degradation of MID1- α4- PP2Ac complex in proteasomes
and thus increase the PP2A protein activity in cells. Through this, tau is dephosphorylated and stabilized in
microtubules as PP2A is the main phosphatase to dephosphorylate tau. Tau protein dephosphorylation
promotes normal cell metabolism and maintains cell structure of microtubules, preventing cell malfunction
and synaptic impairment. This also prevents the formation of the toxic neurofibrillary tangles that damage
neurons, and thus the progression of the disease. The purpose of the study was to characterize MID1 as a
drug target for small-molecule inhibitors and study how the MID1 modification affects PP2A levels and
MID1-α4 -interaction.
The research included MID1 validation and compound testing done at the same time. The experiment started
with the validation of MID1 as a drug target. The aim was to silence MID1 from human embryonic kidney
293 cells by using commercial MID1 small interfering RNA (siRNA). Although the results obtained were
not statistically significant, the association between MID1 and PP2A is noticeable with the MolPort 6
inhibitor compound.
Key words: Neurodegenerative diseases, MID1-α4-PP2Ac complex, MID1-inhibitors.
die. Alzheimer’s and Parkinson’s diseases are the most prevalent and well-known NDs. Current treatments
alleviate the symptoms but are unable to slow the progression of the disease or the destruction of the nerve
cells. Therefore, finding novel therapies that could modify the course of neurodegenerative diseases is
important.
Midline 1 (MID1), a ubiquitin ligase, is a novel potential target for drug development. The protein forms a
complex with protein phosphatase 2A (PP2A) and its subunit α4 and transports them to proteasomes for
degradation. MID1-inhibitors aim to prevent the degradation of MID1- α4- PP2Ac complex in proteasomes
and thus increase the PP2A protein activity in cells. Through this, tau is dephosphorylated and stabilized in
microtubules as PP2A is the main phosphatase to dephosphorylate tau. Tau protein dephosphorylation
promotes normal cell metabolism and maintains cell structure of microtubules, preventing cell malfunction
and synaptic impairment. This also prevents the formation of the toxic neurofibrillary tangles that damage
neurons, and thus the progression of the disease. The purpose of the study was to characterize MID1 as a
drug target for small-molecule inhibitors and study how the MID1 modification affects PP2A levels and
MID1-α4 -interaction.
The research included MID1 validation and compound testing done at the same time. The experiment started
with the validation of MID1 as a drug target. The aim was to silence MID1 from human embryonic kidney
293 cells by using commercial MID1 small interfering RNA (siRNA). Although the results obtained were
not statistically significant, the association between MID1 and PP2A is noticeable with the MolPort 6
inhibitor compound.
Key words: Neurodegenerative diseases, MID1-α4-PP2Ac complex, MID1-inhibitors.