DNALI1 Promotes Neurodegeneration after Traumatic Brain Injury via Inhibition of Autophagosome‐Lysosome Fusion
AbstractTraumatic 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.
期刊:
Advanced Science
2024
作者:
Xulong Ding,Shuqiang Cao,Qing Wang,Bin Du,Kefeng Lu,Shiqian Qi,Ying Cheng,Qing‐Zhang Tuo,Weibo Liang,Peng Lei
DOI:10.1002/advs.202306399
Leucine‐rich repeat kinase 2 (LRRK2) inhibition upregulates microtubule‐associated protein 1B to ameliorate lysosomal dysfunction and parkinsonism
AbstractMutations in LRRK2 (encoding leucine‐rich repeat kinase 2 protein, LRRK2) are the most common genetic risk factors for Parkinson's disease (PD), and increased LRRK2 kinase activity was observed in sporadic PD. Therefore, inhibition of LRRK2 has been tested as a disease‐modifying therapeutic strategy using the LRRK2 mutant mice and sporadic PD. Here, we report a newly designed molecule, FL090, as a LRRK2 kinase inhibitor, verified in cell culture and animal models of PD. Using the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mice and SNCA A53T transgenic mice, FL090 ameliorated motor dysfunctions, reduced LRRK2 kinase activity, and rescued loss in the dopaminergic neurons in the substantia nigra. Notably, by RNA‐Seq analysis, we identified microtubule‐associated protein 1 (MAP1B) as a crucial mediator of FL090's neuroprotective effects and found that MAP1B and LRRK2 co‐localize. Overexpression of MAP1B rescued 1‐methyl‐4‐phenylpyridinium induced cytotoxicity through rescuing the lysosomal function, and the protective effect of FL090 was lost in MAP1B knockout cells. Further studies may be focused on the in vivo mechanisms of MAP1B and microtubule function in PD. Collectively, these findings highlight the potential of FL090 as a therapeutic agent for sporadic PD and familial PD without LRRK2 mutations.
期刊:
MedComm
2023
作者:
Kang Chen,Fei Tang,Bin Du,Zhe‐Zhou Yue,Ling‐Ling Jiao,Xu-Long Ding,Qing‐Zhang Tuo,Jie Meng,Si‐Yu He,Lunzhi Dai,Peng Lei,Xia‐Wei Wei
DOI:10.1002/mco2.429
