The leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of autosomal-dominant Parkinson disease (PD). Mitochondrial dysfunction represents a critical event in the pathogenesis of PD. We demonstrated that wild-type (WT) LRRK2 expression caused mitochondrial fragmentation along with increased mitochondrial dynamin-like protein (DLP1, also known as DRP1), a fission protein, which was further exacerbated by expression of PD-associated mutants (R1441C or G2019S) in both SH-SY5Y and differentiated primary cortical neurons. We also found that LRRK2 interacted with DLP1, and LRRK2–DLP1 interaction was enhanced by PD-associated mutations that probably results in increased mitochondrial DLP1 levels. Co-expression of dominant-negative DLP1 K38A or WT Mfn2 blocked LRRK2-induced mitochondrial fragmentation, mitochondrial dysfunction and neuronal toxicity. Importantly, mitochondrial fragmentation and dysfunction were not observed in cells expressing either GTP-binding deficient mutant LRRK2 K1347A or kinase-dead mutant D1994A which has minimal interaction with DLP1 and did not increase the mitochondrial DLP1 level. We concluded that LRRK2 regulates mitochondrial dynamics by increasing mitochondrial DLP1 through its direct interaction with DLP1, and LRRK2 kinase activity plays a critical role in this process.
Wang, Xinglong; Yan, Michael H.; Fujioka, Hisashi; Liu, Jun; Wilson-Delfosse, Amy; Chen, Shu G.; Perry, George; Casadesus, Gemma; Zhu, Xiongwei
Bacterial heat-labile (LT) enterotoxins signal through tightly regulated interactions with host cell gangliosides. LT-IIa and LT-IIb of Escherichia coli bind preferentially to gangliosides with a NeuAcα2-3Galβ1-3GalNAc terminus, with key distinctions in specificity. LT-IIc, a newly discove ... more
Phosphate deficiency is characteristic for many natural habitats, resulting in different physiological responses in plants and bacteria including the replacement of phospholipids by glycolipids and other phosphorous-free lipids. The plant pathogenic bacterium Agrobacterium tumefaciens, whi ... more
A tryptophan side chain was introduced into subsite +1 of family GH-18 (class V) chitinases from Nicotiana tabacum and Arabidopsis thaliana (NtChiV and AtChiC, respectively) by the mutation of a glycine residue to tryptophan (G74W-NtChiV and G75W-AtChiC). The specific activity toward glyco ... more