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. 2018 Nov 13;4(6):e288.
doi: 10.1212/NXG.0000000000000288. eCollection 2018 Dec.

Lysosomal dysfunction in TMEM106B hypomyelinating leukodystrophy

Yoko Ito  1 , Taila Hartley  1 , Stephen Baird  1 , Sunita Venkateswaran  1 , Cas Simons  1 , Nicole I Wolf  1 , Kym M Boycott  1 , David A Dyment  1 , Kristin D Kernohan  1
Affiliations

Lysosomal dysfunction in TMEM106B hypomyelinating leukodystrophy

Yoko Ito et al. Neurol Genet. .
No abstract available

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Figures

Figure
Figure. Lysosome dysfunction observed in patient-derived fibroblasts with the TMEM106B p.Asp252Asn substitution
(A) Control and patient fibroblasts had comparable levels of both mRNA and TMEM106B protein when examined by real-time quantitative PCR and western blot analysis, respectively (p > 0.05, 2-tailed Student's t-test). (B) An increase in the lysosome-specific marker LAMP1 was observed in patient cells by both Western blot analysis and immunofluorescent staining (p < 0.001, 2-tailed Student's t-test). (A substantial decrease was observed in the number of lysotracker-positive spots in the patient cells by immunofluorescence; p < 0.001, 2-tailed Student's t-test.) For immunofluorescent studies, fibroblast images were collected from 10 wells per sample from 3 independent experiments using the Opera High Content Screening System (Perkin Elmer) and analyzed using Columbus software. Scale bars represent 10 μm. Three control fibroblast cell lines were used for these studies. (C) Western blot analyses showed an accumulation of the intermediate forms of both cathepsin B and cathepsin L, but accumulation of only the mature form of cathepsin L in patient fibroblasts. The mature form of cathepsin B is not detectable by Western blot analysis in patient cells. (D) A fluorescence-based enzyme assay shows reduction in the activity of cathepsin B in affected fibroblasts (p < 0.05, 1-way analysis of variance, Bonferroni post-test).
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References

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