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КартаВръзкиТемиБългарияНощта (K-TRIO)Мария Склодовска-КюриЗа ученициЗа учителиМетодологияИзненадай ме
HEИндивидуална стипендия2023–2025

PARTHECOM · New pathway and small-molecule compounds for Parkinson’s disease therapy

„Хоризонт Европа“ — Действия „Мария Склодовска-Кюри“

Период
2023-09-01 → 2025-11-30
Финансиране от ЕС
215 534 €
Участници
2
Схема
HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Нови химични съединения, които активират протеина METTL3, се тестват за защита на допаминовите неврони в мозъка. Това може да помогне за създаването на лекарства, които преминават кръвно-мозъчната бариера и облекчават симптомите на болестта на Паркинсон.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

New pathway and small-molecule compounds for Parkinson’s disease therapy

Parkinson’s disease (PD) is a neurodegenerative disorder which affects more than 10 million people around the world. It is characterised by gradual degeneration and loss of nigrostriatal dopamine (DA) neurons. This results in motor symptoms like rigidity and tremors but also non-motor symptoms like constipation, depression etc. The is no cure for this disease, only alleviation of symptoms is possible. Although experimental administration of neurotrophic factors has shown some promise, they need to be delivered directly into the brain, making the procedure risky and expensive. Importantly, delivery into the brain will not affect non-motor symptoms. Thus, there is a need for drugs that could be delivered systemically and that would cross the blood-brain barrier. Although the aetiology of PD is unknown, certain toxins and mutations are known to contribute. In addition, recent evidence points to a decrease in the methylation of mRNA at adenosine position N6 (m6A). This reversible modification, which is catalysed by methyltransferase like 3 (METTL3), is enriched in neurons and cancer cells affecting the stability, transport and translation of mRNAs. Our collaborators have developed novel compounds that activate METTL3 and thereby increase cellular m6A levels on mRNA (m6A enhancers). Preliminary testing of these compounds indicated their neuroprotective properties on DA neurons. The main aim of this project was to solidify the importance of mRNA m6A in DA neuron survival. Further, the mechanism of action of how increasing m6A protects neurons was investigated. Finally, the ability of the compounds to penetrate the blood-brain barrier was evaluated. These experiments uncover a completely new pathway for DA neuron protection and pave way for novel therapeutic avenues against PD.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Parkinson’s disease (PD) is a neurodegenerative disease with growing incidence. More than 10 million people worldwide are affected by this condition. In addition to decline in the patients’ quality of life, the economic burden of PD is estimated to exceed 13,9 billion EUR in EU annually. Considering this, novel and more efficient therapeutic options are needed, as current PD treatments alleviate symptoms without stopping neurodegeneration and progression of the disease. Although the etiology of PD is unclear, degeneration of dopamine (DA) neurons has been shown to result from certain genetic mutations, toxins and pathological protein aggregation among others. Importantly, recent evidence points to decrease in mRNA methylation at adenosine N6 (m6A) in PD. Data also indicate that m6A reduction may induce DA neuron apoptosis.Prof. Mart Saarma and collaborators have discovered that m6A methylation is a crucial regulator of neuronal apoptosis. They developed novel m6A methyltransferase activators and demethylase inhibitors that potently enhance mRNA m6A levels. Importantly, preliminary data show that these compounds protect DA neurons from neurotoxin-induced death in culture at nanomolar concentration. Moreover, one compound tested thus far remarkably improves motor behavior, protects and regenerates DA neurons and their axons in rat PD model more potently than “gold standard” GDNF. Considering this, the current project aims to elucidate the mechanisms how m6A regulates DA neuron survival and axonal regeneration. We will identify for the first time the mRNAs with increased/decreased methylation at adenosine N6 that regulate the life and death of DA neurons, thereby potentially opening new directions in PD research. In addition, we aim to provide completely new lead molecules for PD treatment.In conclusion, the current project aims to broaden our understanding on the mechanisms of Parkinson’s disease and provide new drug candidates for novel PD therapeutic avenues.

Оригинален текст от CORDIS (на английски).

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Данни: CORDIS, © Европейски съюз