Linking Protein Misfolding and Heat Stress: A Common Role for the Kynurenine Pathway

蛋白质错误折叠与热应激之间的联系：犬尿氨酸途径的共同作用

Dorothy Wasike, Petra Majerová, Timotej Jankech, Andrej Kováč (2026) Linking Protein Misfolding and Heat Stress: A Common Role for the Kynurenine Pathway Preprints.org

Abstract

Kynurenine pathway (KP) of trytophan metabolism is emerging as a key regulator of immune response, neuroinflammation, and neurodegenration. Tryptophan derived metabolites influence multiple processes including excitotoxicty, oxidative stress, mitochondrial dysfunction, and protein aggregation which are underlying mechanisms in major neurological disorders. The dysregulation of the KP leads to an imbalance between neuroprotective metabolites such as kynurenic acid and neurotoxic metabolites including quinolinic acid and 3-hydroxykyrunine, contributing to neuronal dysfunction and disease progression. This imbalance is associated with chronic proteinopathies such as Alzeihmer‘s disease and Parkinson‘s disease, where persistent neuroinflammation and excitotoxicty sustain the activation of KP and subsequent neurodegenaration. Importantly, KP activation is not only limited to chronic conditions but also occurs in acute neurological insults such as heatstroke, where impaired thermoregulation contributes to systemic inflammatory responses, oxidative stress, and disruption of the blood-brain barrier. Consequently, this facilitates the influx of peripheral kyrunine into the brain and its conversion into neuroactive metabolites, linking peripheral immune activation and neuronal injury. These findings highlight KP as mechanistic bridge between acute and chronic neuropathological processes. In addition, the KP involvement in NAD⁺ production links immune activation and cellular energy metabolism, subsequently increasing neuronal vulnerability, particularly under stress. Emerging evidence further support the potential of KP metabolites as diagnostic biomarkers for disease progression and severity, as well as possible therapeutic targets. Targeting key enzymes within the KP may offer novel strategies to reduce neurotoxicity, and restore metabolic balance which subsequently improves clinical outcomes.

色氨酸代谢的犬尿氨酸途径（KP）正逐渐成为免疫反应、神经炎症和神经退行性疾病的关键调节因子。色氨酸衍生的代谢产物影响多种过程，包括兴奋性毒性、氧化应激、线粒体功能障碍和蛋白质聚集，这些都是主要神经系统疾病的潜在机制。KP的失调会导致神经保护性代谢产物（如犬尿酸）与神经毒性代谢产物（如喹啉酸和3-羟基犬尿氨酸）之间的失衡，从而导致神经元功能障碍和疾病进展。这种失衡与阿尔茨海默病和帕金森病等慢性蛋白病相关，在这些疾病中，持续的神经炎症和兴奋性毒性会维持KP的激活，进而导致神经退行性变。重要的是，KP 的激活不仅限于慢性疾病，也发生在急性神经损伤（例如中暑）中。在中暑中，体温调节受损会导致全身炎症反应、氧化应激和血脑屏障破坏。因此，这促进了外周血中的犬尿氨酸流入大脑并转化为神经活性代谢物，从而将外周免疫激活与神经元损伤联系起来。这些发现凸显了 KP 作为连接急性和慢性神经病理过程的机制桥梁的作用。此外，KP 参与 NAD⁺ 的生成，从而将免疫激活和细胞能量代谢联系起来，进而增加神经元的脆弱性，尤其是在应激条件下。越来越多的证据进一步支持 KP 代谢物作为疾病进展和严重程度的诊断生物标志物以及潜在治疗靶点的潜力。靶向 KP 中的关键酶可能为降低神经毒性、恢复代谢平衡提供新的策略，从而改善临床疗效。

Links

https://doi.org/10.20944/preprints202604.0589.v1
http://dx.doi.org/10.20944/preprints202604.0589.v1

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