DNA 'glue' could help prevent and treat diseases triggered by ageing

Macquarie University Discovers Natural Protein That Powerfully Repairs Damaged DNA: Researchers at Macquarie University have identified a protein in human cells—protein disulfide isomerase (PDI)—that acts like a "glue" to help mend broken DNA. Published in Ageing Cell, this finding could lead to new therapies for age-related diseases such as motor neuron disease (MND), Alzheimer's, and Parkinson's.

DNA Needs Constant Repair

• Every day, our cells incur tiny DNA lesions from normal metabolism and external stressors (UV light, pollution).

• As we age, repair mechanisms weaken and damage accumulates, driving aging and disease.

PDI's New Role

• PDI normally works in the endoplasmic reticulum to fold proteins properly.

• The team discovered that when DNA suffers a double-strand break, PDI relocates to the nucleus and directly participates in gluing the broken ends back together.

• In lab tests, cells without PDI failed to repair damage effectively, but adding PDI back restored their repair capacity.

Animal Studies Confirm Benefits

• In live zebrafish, boosting PDI levels protected them from age-related DNA damage.

• This suggests future gene- or mRNA-based therapies (similar to COVID-19 vaccines) could enhance our cells' own repair systems.

PDI's Dual Identity

• In healthy cells, PDI repairs DNA and prevents disease.

• In cancer cells, PDI can be hijacked to repair tumor DNA, helping cancer resist chemotherapy.

• Therapies will need to precisely inhibit PDI in tumors while boosting it in neurons where DNA repair is most crucial.

Looking Ahead

• Dr. Sina Shadfar's team is developing targeted gene and mRNA delivery to enhance DNA repair in brain cells.

• Supported by Australia's leading MND research charity, this is the country's first mRNA-based therapy project aimed at tackling neurodegeneration through aging mechanisms.

With populations aging worldwide, neurodegenerative disease rates and mortality are rising. Strengthening our cells' natural DNA repair offers not only a way to combat aging but also the potential to prevent or slow serious diseases—opening exciting new avenues for treatment.

麥覺理大學發現一種天然蛋白，能強力修復受損 DNA

麥覺理大學的研究人員發現，存在於人體細胞中的蛋白質——二硫鍵異構酶（PDI），在修復斷裂的 DNA 時，就像「黏合劑」一樣發揮作用。這項成果發表在《Ageing Cell》期刊，或許能為運動神經元疾病（MND）、阿茲海默症、帕金森氏症等年齡相關疾病帶來新療法。

DNA 要時時修補

• 我們的細胞每天都受內部代謝和外部刺激（如紫外線、污染）帶來的 DNA 微小損傷。

• 年紀越大，修復能力越差，損傷累積後就容易引發老化和疾病。

PDI 的新角色

• PDI 原本只在細胞的內質網幫助蛋白摺疊。

• 研究發現，遇到 DNA 的雙股斷裂時，PDI 會移到細胞核，直接參與修復斷裂的 DNA 兩端。

• 實驗中，移除 PDI 的細胞無法有效修復，補回 PDI 後修復能力大幅提升。

動物實驗驗證效果

• 在活體斑馬魚中，提高 PDI 水平能保護它們免受年齡相關的 DNA 傷害。

• 這說明未來有機會用基因或 mRNA 技術（如 COVID-19 疫苗使用的方法），增強人體細胞自身的修復功能。

PDI 的雙重身分

• 在健康細胞中，PDI 修復 DNA、預防病變。

• 在癌細胞裡，PDI 卻被利用來修復腫瘤 DNA，幫助癌細胞抗拒化療。

• 未來要精準調控 PDI：抑制癌細胞中的 PDI，同時在神經細胞中提升它的修復作用。

未來展望

• Dr. Sina Shadfar 團隊正開發精準遞送基因與 mRNA療法，專門針對大腦細胞中 DNA 修復機制。

• 這些研究已獲得澳洲 MND 研究組織資助，是澳洲首例 mRNA 基因療法計畫，目標是提早介入、阻止神經退化疾病的進展。

隨著人口老化，神經退化性疾病的發病率和死亡率都在上升。增強 DNA 自我修復能力，不僅能對抗老化，更有可能預防或延緩多種嚴重疾病，開創全新的治療方向。