Department of Neurology and State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China.
Center of Translational Medicine and Clinical Laboratory, The Fourth Affiliated Hospital of Soochow University, Medical Center of Soochow University, Suzhou Dushu Lake Hospital, Suzhou, Jiangsu, 215123, China.
Adv Sci (Weinh). 2024 Apr;11(15):e2306399. doi: 10.1002/advs.202306399. Epub 2024 Feb 13.
Traumatic brain injury (TBI) leads to progressive neurodegeneration that may be caused by chronic traumatic encephalopathy (CTE). However, the precise mechanism remains unclear. Herein, the study identifies a crucial protein, axonemal dynein light intermediate polypeptide 1 (DNALI1), and elucidated its potential pathogenic role in post-TBI neurodegeneration. The DNALI1 gene is systematically screened through analyses of Aging, Dementia, and TBI studies, confirming its elevated expression both in vitro and in vivo. Moreover, it is observed that altered DNALI1 expression under normal conditions has no discernible effect. However, upon overexpression, DNALI1 inhibits autophagosome-lysosome fusion, reduces autophagic flux, and exacerbates cell death under pathological conditions. DNALI1 silencing significantly enhances autophagic flux and alleviates neurodegeneration in a CTE model. These findings highlight DNALI1 as a potential key target for preventing TBI-related neurodegeneration.
创伤性脑损伤（TBI）导致进行性神经退行性变，可能由慢性创伤性脑病（CTE）引起。然而，确切的机制尚不清楚。在此，本研究确定了一个关键蛋白，轴丝动力蛋白轻中间多肽 1（DNALI1），并阐明了其在创伤后神经退行性变中的潜在致病作用。通过对衰老、痴呆和 TBI 研究的分析，系统筛选了 DNALI1 基因，证实其在体外和体内均呈高表达。此外，还观察到在正常条件下改变 DNALI1 的表达没有明显的影响。然而，过表达时，DNALI1 抑制自噬体-溶酶体融合，降低自噬流，并在病理条件下加剧细胞死亡。DNALI1 沉默可显著增强自噬流并减轻 CTE 模型中的神经退行性变。这些发现强调了 DNALI1 作为预防与 TBI 相关的神经退行性变的潜在关键靶标。
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