History, genetic, and recent advances on Krabbe disease

Graziano, Adriana Carol Eleonora; Cardile, Venera

doi:10.1016/j.gene.2014.09.046

Cited by 121 publications

(118 citation statements)

References 132 publications

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“…The first phenotype observed in the TWI mouse muscle is the reduction of muscular size, which is in agreement with the global weight loss observed 30, 31 . We quantified the area of single myofibers (Fig.…”

Section: Resultssupporting

confidence: 83%

Ultrastructural Characterization of the Lower Motor System in a Mouse Model of Krabbe Disease

Cappello

Marchetti

Parlanti

et al. 2016

Sci Rep

15,621

331

6,510

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Krabbe disease (KD) is a neurodegenerative disorder caused by the lack of β- galactosylceramidase enzymatic activity and by widespread accumulation of the cytotoxic galactosyl-sphingosine in neuronal, myelinating and endothelial cells. Despite the wide use of Twitcher mice as experimental model for KD, the ultrastructure of this model is partial and mainly addressing peripheral nerves. More details are requested to elucidate the basis of the motor defects, which are the first to appear during KD onset. Here we use transmission electron microscopy (TEM) to focus on the alterations produced by KD in the lower motor system at postnatal day 15 (P15), a nearly asymptomatic stage, and in the juvenile P30 mouse. We find mild effects on motorneuron soma, severe ones on sciatic nerves and very severe effects on nerve terminals and neuromuscular junctions at P30, with peripheral damage being already detectable at P15. Finally, we find that the gastrocnemius muscle undergoes atrophy and structural changes that are independent of denervation at P15. Our data further characterize the ultrastructural analysis of the KD mouse model, and support recent theories of a dying-back mechanism for neuronal degeneration, which is independent of demyelination.

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Section: Resultssupporting

confidence: 83%

Ultrastructural Characterization of the Lower Motor System in a Mouse Model of Krabbe Disease

Cappello

Marchetti

Parlanti

et al. 2016

Sci Rep

15,621

331

6,510

View full text Add to dashboard Cite

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“…While frequently detected in infants, KD has also been found as an adult-onset disease [1, 2]. Compared to rapid clinical progression in infants, adult-onset KD patients show less severe phenotype with slower disease progression [2].…”

Section: Introductionmentioning

confidence: 99%

Patient fibroblasts-derived induced neurons demonstrate autonomous neuronal defects in adult-onset Krabbe disease

Lim

Choi

et al. 2016

Oncotarget

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Krabbe disease (KD) is an autosomal recessive neurodegenerative disorder caused by defective β-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.

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“…Krabbe disease (globoid cell leukodystrophy) (KD; OMIM 245200) is a devastating autosomal recessive neurometabolic condition caused by lysosomal galactocerebrosidase deficiency (GALC; EC 3.2.1.46), responsible for cleavage of galactosyl moieties from its four substrates: galactosylceramide, lactosylceramide, lactosylsphingosine, and psychosine [37]. It is a rare (1/100,000 prevalence) [12] and demyelinating pathology where non-degraded substrates accumulate in the central and peripheral nervous systems with severe psychiatric and neuromotor consequences.…”

Section: Role Of Biomarkers In the Study Of Lsdsmentioning

confidence: 99%

Biomarkers in Lysosomal Storage Diseases

2016

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A biomarker is generally an analyte that indicates the presence and/or extent of a biological process, which is in itself usually directly linked to the clinical manifestations and outcome of a particular disease. The biomarkers in the field of lysosomal storage diseases (LSDs) have particular relevance where spectacular therapeutic initiatives have been achieved, most notably with the introduction of enzyme replacement therapy (ERT). There are two main types of biomarkers. The first group is comprised of those molecules whose accumulation is directly enhanced as a result of defective lysosomal function. These molecules represent the storage of the principal macro-molecular substrate(s) of a specific enzyme or protein, whose function is deficient in the given disease. In the second group of biomarkers, the relationship between the lysosomal defect and the biomarker is indirect. In this group, the biomarker reflects the effects of the primary lysosomal defect on cell, tissue, or organ functions. There is no “gold standard” among biomarkers used to diagnosis and/or monitor LSDs, but there are a number that exist that can be used to reasonably assess and monitor the state of certain organs or functions. A number of biomarkers have been proposed for the analysis of the most important LSDs. In this review, we will summarize the most promising biomarkers in major LSDs and discuss why these are the most promising candidates for screening systems.

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History, genetic, and recent advances on Krabbe disease

Cited by 121 publications

References 132 publications

Ultrastructural Characterization of the Lower Motor System in a Mouse Model of Krabbe Disease

Ultrastructural Characterization of the Lower Motor System in a Mouse Model of Krabbe Disease

Patient fibroblasts-derived induced neurons demonstrate autonomous neuronal defects in adult-onset Krabbe disease

Biomarkers in Lysosomal Storage Diseases

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