오기욱
2019-03-14T08:14:51Z
2019-03-14T08:14:51Z
2016-11
ONCOTARGET, v. 7, NO 46, Page. 74496-74509
1949-2553
http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=12812&path[]=40592
https://repository.hanyang.ac.kr/handle/20.500.11754/100806
Krabbe disease (KD) is an autosomal recessive neurodegenerative disorder caused by defective beta-galactosylceramidase (GALC), a lysosomal enzyme responsible for cleavage of several key substrates including psychosine. Accumulation of psychosine to the cytotoxic levels in KD patients is thought to cause dysfunctions in myelinating glial cells based on a comprehensive study of demyelination in KD. However, recent evidence suggests myelin-independent neuronal death in the murine model of KD, thus indicating defective GALC in neurons as an autonomous mechanism for neuronal cell death in KD. These observations prompted us to generate induced neurons (iNeurons) from two adult-onset KD patients carrying compound heterozygous mutations (p.[K563*];[L634S]) and (p.[N228_S232delinsTP];[G286D]) to determine the direct contribution of autonomous neuronal toxicity to KD. Here we report that directly converted KD iNeurons showed not only diminished GALC activity and increased psychosine levels, as expected, but also neurite fragmentation and abnormal neuritic branching. The lysosomal-associated membrane proteins 1 (LAMP1) was expressed at higher levels than controls, LAMP1-positive vesicles were significantly enlarged and fragmented, and mitochondrial morphology and its function were altered in KD iNeurons. Strikingly, we demonstrated that psychosine was sufficient to induce neurite defects, mitochondrial fragmentation, and lysosomal alterations in iNeurons derived in healthy individuals, thus establishing the causal effect of the cytotoxic GALC substrate in KD and the autonomous neuronal toxicity in KD pathology.
This work is supported in part by grants from the Korean Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (HI12C0135), the US National Human Genome Research Institute grant (HG004659) to X-D.F, and the National Research Foundation of Korea (NRF) grants funded by the Korean government, MSIP (NRF-2014R1A2A2A01004240).
ko_KR
IMPACT JOURNALS LLC
krabbe disease
globoid cell leukodystrophy
beta-galactosylceramidase
psychosine
induced neuron
Gerotarget
Patient fibroblasts-derived induced neurons demonstrate autonomous neuronal defects in adult-onset Krabbe disease
Article
46
7
10.18632/oncotarget.12812
74496-74509
ONCOTARGET
Lim, Su Min
Choi, Byung-Ok
Oh, Seong-Il
Choi, Won Jun
Oh, Ki-Wook
Nahm, Minyeop
Xue, Yuanchao
Choi, Jae Hyeok
Choi, Ji Young
Kim, Young-Eun
2016010107
S
COLLEGE OF MEDICINE[S]
DEPARTMENT OF MEDICINE
kiwook-oh
E-6996-2017
http://orcid.org/0000-0001-6011-629X