Live-cell superresolution pathology reveals different molecular mechanisms of pelizaeus-merzbacher disease

Zheng, Xuan; Duan, Ruoyu; Li, Liuju; Xing, Shijia; Ji, Haoran; Yan, Huifang; Gao, Kai; Wang, Jianyong; Wang, Jingmin; Chen, Liangyi

doi:10.1016/j.scib.2020.08.016

Cited by 6 publications

(4 citation statements)

References 13 publications

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“…A proline mutation results an α-helix turning and thus alteration of the PLP1 structure [ 31 ], which can explain why P173S corresponds to group A. Moreover, different PLP1 mutants exhibited distinct localizations, and the pathogenic mechanisms of F32L, T118R, T156I, P173S, R205K, G208V and G208D were demonstrated in our other study [ 32 ].…”

Section: Discussionmentioning

confidence: 74%

Genotype–phenotype correlation and natural history analyses in a Chinese cohort with pelizaeus–merzbacher disease

Duan

Yan

et al. 2022

Orphanet J Rare Dis

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Background The natural history and genotype–phenotype correlation of Pelizaeus–Merzbacher disease (PMD) of Chinese patients has been rarely reported. Method Patients who met the criteria for PMD were enrolled in our study. Genomic analysis was conducted by multiplex ligation probe amplification (MLPA) and Sanger or whole-exome sequencing (WES). Natural history differences and genotype–phenotype correlations were analyzed. Result A total of 111 patients were enrolled in our follow-up study. The median follow-up interval was 53 m (1185). Among PMD patients, developmental delay was the most common sign, and nystagmus and hypotonia were the most common initial symptoms observed. A total of 78.4% of the patients were able to control their head, and 72.1% could speak words. However, few of the patients could stand (9.0%) or walk (4.5%) by themselves. Nystagmus improved in more than half of the patients, and hypotonia sometimes deteriorated to movement disorders. More PLP1 point mutations patients were categorized into severe group, while more patients with PLP1 duplications were categorized into mild group (p < 0.001). Compared to patients in mild groups, those in the severe group had earlier disease onset and had acquired fewer skills at a later age. Conclusion PMD patients have early disease onset with nystagmus and hypotonia followed by decreased nystagmus and movement disorders, such as spasticit. Patients with PLP1 duplication were more likely to be categorized into the mild group, whereas patients with point mutations were more likely to be categorized into the severe group.

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Section: Discussionmentioning

confidence: 74%

Genotype–phenotype correlation and natural history analyses in a Chinese cohort with pelizaeus–merzbacher disease

Duan

Yan

et al. 2022

Orphanet J Rare Dis

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“…Getting accurate physiological knowledge requires studying cells within their parent organisms, and thus scientific researchers could obtain the biological information in a native state within the organism itself, where all the cues are driven by gene expression ( Liu et al, 2018 ). While many of the structures and organization patterns of biomolecules in in-vitro cells have been identified, in vivo studies will offer unique insights into the cellular morphology in relation to genetical conditions or pathological modifications ( Vacaru et al, 2014 ; Stone et al, 2017 ; Zheng et al, 2020 ). However, at present, it is still a challenge to observe the organelles and macromolecular complexes in vivo at high resolution.…”

Section: Introductionmentioning

confidence: 99%

Super-Resolution Microscopy: Shedding New Light on In Vivo Imaging

Jing

Zhang

et al. 2021

Front. Chem.

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Over the past two decades, super-resolution microscopy (SRM), which offered a significant improvement in resolution over conventional light microscopy, has become a powerful tool to visualize biological activities in both fixed and living cells. However, completely understanding biological processes requires studying cells in a physiological context at high spatiotemporal resolution. Recently, SRM has showcased its ability to observe the detailed structures and dynamics in living species. Here we summarized recent technical advancements in SRM that have been successfully applied to in vivo imaging. Then, improvements in the labeling strategies are discussed together with the spectroscopic and chemical demands of the fluorophores. Finally, we broadly reviewed the current applications for super-resolution techniques in living species and highlighted some inherent challenges faced in this emerging field. We hope that this review could serve as an ideal reference for researchers as well as beginners in the relevant field of in vivo super resolution imaging.

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Section: Introductionmentioning

confidence: 98%

“…Previous studies have shown different pathogenic mechanisms resulting from point and duplication mutations of PLP1 [3][4][5], respectively. Point mutations lead to misfolded protein accumulation in the endoplasmic reticulum (ER), triggering an unfolded protein response (UPR) pathway or defective tra cking and fusion of mutated PLP1 [5]. A larger proportion of the cases, however, have been associated with duplication mutations: almost 70% of PMD cases can be attributed to PLP1 duplication and approximately 25% to point mutations [6,7].…”

Section: Introductionmentioning

confidence: 98%

Novel insight into the potential pathogenicity of mitochondrial dysfunction resulting from PLP1 duplication mutations in patients with Pelizaeus–Merzbacher disease

Duan

Yan

et al. 2021

Preprint

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Among the hypomyelinating leukodystrophies, Pelizaeus–Merzbacher disease (PMD) is a representative disorder. The disease is caused by different types of PLP1 mutations, among which PLP1 duplication accounts for ~ 70% of the mutations. Previous studies have shown that PLP1 duplications lead to PLP1 retention in the endoplasmic reticulum (ER); in parallel, recent studies have demonstrated that PLP1 duplication can also lead to mitochondrial dysfunction. As such, the respective roles and interactions of the ER and mitochondria in the pathogenesis of PLP1 duplication are not clear. In both PLP1 patients’ and healthy fibroblasts, we measured mitochondrial respiration with a Seahorse XF Extracellular Analyzer and examined the interactions between the ER and mitochondria with super-resolution microscopy (spinning-disc pinhole-based structured illumination microscopy, SD-SIM). For the first time, we demonstrated that PLP1 duplication mutants had closer ER-mitochondrion interfaces mediated through structural and morphological changes in both the ER and mitochondria-associated membranes (MAMs). These changes in both the ER and mitochondria then led to mitochondrial dysfunction, as reported previously. This work highlights the roles of MAMs in bridging PLP1 expression in the ER and pathogenic dysfunction in mitochondria, providing novel insight into the pathogenicity of mitochondrial dysfunction resulting from PLP1 duplication. These findings suggest that interactions between the ER and mitochondria may underlie pathogenic mechanisms of hypomyelinating leukodystrophies diseases at the organelle level.

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Live-cell superresolution pathology reveals different molecular mechanisms of pelizaeus-merzbacher disease

Cited by 6 publications

References 13 publications

Genotype–phenotype correlation and natural history analyses in a Chinese cohort with pelizaeus–merzbacher disease

Genotype–phenotype correlation and natural history analyses in a Chinese cohort with pelizaeus–merzbacher disease

Super-Resolution Microscopy: Shedding New Light on In Vivo Imaging

Novel insight into the potential pathogenicity of mitochondrial dysfunction resulting from PLP1 duplication mutations in patients with Pelizaeus–Merzbacher disease

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