Altered Trafficking and Processing of GALC Mutants Correlates with Globoid Cell Leukodystrophy Severity

被引:29
作者
Shin, Daesung [1 ,2 ]
Feltri, M. Laura [1 ,2 ,3 ]
Wrabetz, Lawrence [1 ,2 ,3 ]
机构
[1] SUNY Buffalo, Hunter James Kelly Res Inst, Buffalo, NY 14203 USA
[2] SUNY Buffalo, Dept Biochem, Buffalo, NY 14203 USA
[3] SUNY Buffalo, Dept Neurol, Jacob Sch Med & Biomed Sci, Buffalo, NY 14203 USA
基金
美国国家卫生研究院;
关键词
galactosylceramidase; globoid cell leukodystrophy; Krabbe disease; lysosomal processing; lysosomal storage disorders; protein trafficking; ONSET KRABBE-DISEASE; GALACTOCEREBROSIDASE ACTIVITY; BETA-GALACTOSIDASE; JAPANESE PATIENTS; TWITCHER MICE; MUTATIONS; GENE; GALACTOSYLCERAMIDASE; EXPRESSION; OLIGODENDROCYTES;
D O I
10.1523/JNEUROSCI.3095-15.2016
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Globoid cell leukodystrophy (GLD, Krabbe disease) is due to autosomal recessive mutations in the lysosomal enzyme galactosylceramidase (GALC). Many GLD patients develop infantile-onset of progressive neurologic deterioration and death by 2 years of age, whereas others have a later-onset, milder disease. Cord blood transplant slows disease progression much more effectively when performed presymptomatically, highlighting the importance of early diagnosis. Current diagnosis is based on reduced GALC activity, DNA sequence, and clinical examination. However, presymptomatic diagnosis is hampered by imperfect genotype-GALC activity-phenotype correlations. In addition, three polymorphisms in the GALC gene are variably associated with disease mutations and have unknown effects on GALC activity and disease outcome. Here, we study mutations that cause infantile or later-onset GLD, and show that GALC activity is significantly lower in infantile versus later-onset mutants when measured in the lysosomal fraction, but not in whole-cell lysates. In parallel, infantile-onset mutant GALCs showed reduced trafficking to lysosomes and processing than later-onset mutant GALCs. Finally, the cis-polymorphisms also affected trafficking to the lysosome and processing of GALC. These differences potentially explain why the activity of different mutations appears similar in whole-cell extracts from lymphocytes, and suggest that measure of GALC activity in lysosomes may better predict the onset and severity of disease for a given GLD genotype.
引用
收藏
页码:1858 / 1870
页数:13
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