Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease

Fukuda, Tokiko; Ewan, Lindsay; Bauer, Manuel; Mattaliano, Robert J.; Zaal, Kristien J.M.; Ralston, Evelyn; Plötz, Paul H.; Raben, Nina

doi:10.1002/ana.20807

Cited by 268 publications

(215 citation statements)

References 46 publications

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“…Notably, there appeared to be fewer, although much larger lysosomes in comt mutants ( Figure 5, J-L, arrowheads). This enlargement of lysosomes is similar to that observed in cathepsin-D mutants (Khurana et al 2010), as well as in a variety of lysosomal storage diseases (Fukuda et al 2006). The enlarged lysosomes could result from a lack of lysosomal turnover.…”

Section: Comt Mutants Cannot Sustain Autophagysupporting

confidence: 84%

A Neuroprotective Function of NSF1 Sustains Autophagy and Lysosomal Trafficking inDrosophila

2014

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A common feature of many neurodegenerative diseases is the accumulation of toxic proteins that disrupt vital cellular functions. Degradative pathways such as autophagy play an important protective role in breaking down misfolded and long-lived proteins. Neurons are particularly vulnerable to defects in these pathways, but many of the details regarding the link between autophagy and neurodegeneration remain unclear. We previously found that temperature-sensitive paralytic mutants in Drosophila are enriched for those exhibiting age-dependent neurodegeneration. Here we show that one of these mutants, comatose (comt), in addition to locomotor defects, displays shortened lifespan and progressive neurodegeneration, including loss of dopaminerigic (DA) neurons. comt encodes Nethyl-maleimide sensitive fusion protein (NSF1), which has a well-documented role in synaptic transmission. However, the neurodegenerative phenotypes we observe in comt mutants do not appear to depend on defects in synaptic transmission, but rather from their inability to sustain autophagy under stress, due at least in part to a defect in trafficking of lysosomal proteases such as cathepsin-L. Conversely, overexpression of NSF1 rescues a-synuclein-induced toxicity of DA neurons in a model of Parkinson's disease. Our results demonstrate a neuroprotective role for NSF1 that involves mediation of fusion events crucial for degradative pathways such as autophagy, providing greater understanding of cellular dysfunctions common to several neurodegenerative diseases.

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Section: Comt Mutants Cannot Sustain Autophagysupporting

confidence: 84%

A Neuroprotective Function of NSF1 Sustains Autophagy and Lysosomal Trafficking inDrosophila

2014

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“…Furthermore, we have shown that autophagic accumulation in muscle fibers was associated with resistance to enzyme replacement therapy. [21][22][23] We now demonstrate that the underlying skeletal muscle pathology and the extent of autophagy in Pompe patients are similar to those in mice. Autophagy appears to play a major role in the pathogenesis of the disease, a finding that has important implications for the effectiveness of enzyme replacement therapy with the recombinant human acid a-glucosidase.…”

Section: Introductionmentioning

confidence: 51%

“…Eventually, in old mice, the autophagic mass replaced most of the muscle tissue. 20,21 Although the presence of autophagic vacuoles with cytoplasmic degradation products in muscle biopsies from patients with Pompe disease was noted many years ago, 16 the phenomenon has received little attention until recently. 28 We have now established that the abnormal autophagy in skeletal muscle is a major feature in the pathology of the disease in humans.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously suggested that in KO mice, the decrease in the amount of available glucose may trigger local autophagic response in glycolytic type II fibers. 21 Indeed, multiple factors may be at play at different stages of Pompe disease. It is well known that the basal levels of autophagy and the regulation of autophagy are age and organ dependent.…”

Section: Discussionmentioning

confidence: 99%

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Deconstructing Pompe Disease by Analyzing Single Muscle Fibers: “To See a World in a Grain of Sand…”

Raben¹,

Takikita²,

Pittis³

et al. 2007

Autophagy

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Autophagy is a major pathway for delivery of proteins and organelles to lysosomes where they are degraded and recycled. We have previously shown excessive autophagy in a mouse model of Pompe disease (glycogen storage disease type II), a devastating myopathy caused by a deficiency of the glycogen-degrading lysosomal enzyme acid a-glucosidase. The autophagic buildup constituted a major pathological component in skeletal muscle and interfered with delivery of the therapeutic enzyme. To assess the role of autophagy in the pathogenesis of the human disease, we have analyzed vesicles of the lysosomal-degradative pathway in isolated single muscle fibers from Pompe patients. Human myofibers showed abundant autophagosome formation and areas of autophagic buildup of a wide range of sizes. In patients, as in the mouse model, the enormous autophagic buildup causes greater skeletal muscle damage than the enlarged, glycogenfilled lysosomes outside the autophagic regions. Clearing or preventing autophagic buildup seems, therefore, a necessary target of Pompe disease therapy.

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“…The defective autophagy in Pompe disease, which is blatantly evident in muscle fibers and to a certain extent in a cell model, may stem from reduced availability of energy source due to lysosomal glycogen sequestration. 44,45 A disturbed energy metabolism has recently been documented in Pompe patients with the adult form of the disease. 46 The autophagic defect contributes to the pathogenesis of muscle damage and alters trafficking of the replacement enzyme to the lysosome in Pompe disease.…”

Section: Discussionmentioning

confidence: 99%

Defects in calcium homeostasis and mitochondria can be reversed in Pompe disease

Lim

Kakhlon

et al. 2015

Autophagy

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Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease

Abstract: The vastly increased autophagic buildup may be responsible for skeletal muscle damage and prevent efficient trafficking of replacement enzyme to lysosomes.

Cited by 268 publications

References 46 publications

A Neuroprotective Function of NSF1 Sustains Autophagy and Lysosomal Trafficking inDrosophila

A Neuroprotective Function of NSF1 Sustains Autophagy and Lysosomal Trafficking inDrosophila

Deconstructing Pompe Disease by Analyzing Single Muscle Fibers: “To See a World in a Grain of Sand…”

Defects in calcium homeostasis and mitochondria can be reversed in Pompe disease

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