前立腺肥大症や高血圧の治療に一般的に使用されている薬剤が、運動ニューロン疾患の新しい治療法として有望であることが、新しい研究により明らかになった。 A drug typically used to treat enlarged prostates and high blood pressure has shown promise as a potential new therapy for motor neuron disease, according to a new study.
2022-08-11 エディンバラ大学
研究者によれば、この薬剤は、英国で約5,000人の成人が罹患しているこの運動ニューロン疾患 (MND) の進行を遅らせるのに役立つ可能性があるとのことです。平均寿命は、症状が現れてから3年です。
研究チームは、解糖酵素ホスホグリセリン酸キナーゼ 1 (PGK1)というエネルギー産生に関与する酵素(細胞内の活性分子)に着目した。
MNDのゼブラフィッシュモデルでは、遺伝的にゼブラフィッシュのPGK1の量を増やすか、テラゾシンを投与してPGK1の活性を高めると、運動ニューロンの成長が改善されることが示された。
また、テラゾシンはMNDのモデルマウスの運動ニューロンを保護し、生存率を向上させ、麻痺の進行を遅らせることができた。
運動ニューロンを培養し、テラゾシンがエネルギーレベルを増加させることにより、これらの細胞を保護することを実証しました。
<関連情報>
- https://www.ed.ac.uk/news/2022/mnd-terazosin
- https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00384-X/fulltext#
テラゾシンによるホスホグリセリン酸キナーゼ1の標的化は、複数の筋萎縮性側索硬化症モデルにおいて運動ニューロンの表現型を改善する Targeting phosphoglycerate kinase 1 with terazosin improves motor neuron phenotypes in multiple models of amyotrophic lateral sclerosis
Helena Chaytow,Emily Carroll,David Gordon,Yu-Ting Huang,Dinja van der Hoorn,Hannah Louise Smith,Thomas Becker,Catherina Gwynne Becker,Kiterie Maud Edwige Faller,Kevin Talbot,Thomas Henry Gillingwater
eBioMedicine Published:August 10, 2022
DOI:https://doi.org/10.1016/j.ebiom.2022.104202
Summary
Background
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with heterogeneous aetiology and a complex genetic background. Effective therapies are therefore likely to act on convergent pathways such as dysregulated energy metabolism, linked to multiple neurodegenerative diseases including ALS.
Methods
Activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) was increased genetically or pharmacologically using terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS. Multiple disease phenotypes were assessed to determine the therapeutic potential of this approach, including axon growth and motor behaviour, survival and cell death following oxidative stress.
Findings
We have found that targeting a single bioenergetic protein, PGK1, modulates motor neuron vulnerability in vivo. In zebrafish models of ALS, overexpression of PGK1 rescued motor axon phenotypes and improved motor behaviour. Treatment with terazosin, an FDA-approved compound with a known non-canonical action of increasing PGK1 activity, also improved these phenotypes. Terazosin treatment extended survival, improved motor phenotypes and increased motor neuron number in Thy1-hTDP-43 mice. In ESC-derived motor neurons expressing TDP-43M337V, terazosin protected against oxidative stress-induced cell death and increased basal glycolysis rates, while rescuing stress granule assembly.
Interpretation
Our data demonstrate that terazosin protects motor neurons via multiple pathways, including upregulating glycolysis and rescuing stress granule formation. Repurposing terazosin therefore has the potential to increase the limited therapeutic options across all forms of ALS, irrespective of disease cause.
Funding
This work was supported by project grant funding from MND Scotland, the My Name’5 Doddie Foundation, Medical Research Council Doctoral Student Training Fellowship [Ref: BST0010Z] and Academy of Medical Sciences grant [SGL023\1100].
