Enhanced autophagy and mitochondrial aberrations in murine GM1-gangliosidosis

Takamura, Ayumi; Higaki, Kazutaka; Kajimaki, Kenya; Otsuka, Susumu; Ninomiya, Haruaki; Matsuda, Junichiro; Ohno, Kousaku; Suzuki, Yoshiyuki; Nanba, Eiji

doi:10.1016/j.bbrc.2007.12.187

Cited by 126 publications

(119 citation statements)

References 25 publications

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…Our findings are consistent with recent studies indicating autophagic impairment in lysosomal storage disorders such as NPC, GM1-gangliosidosis, and mucopolysaccharidoses (Liao et al, 2007;Pacheco and Lieberman, 2008;Settembre et al, 2008;Takamura et al, 2008). Thus, the autophagic-lysosomal dysfunction could initiate a pathogenic cascade by impaired recycling of metabolites and accumulation of cellular waste products ultimately leading to neurodegeneration.…”

supporting

confidence: 93%

Sphingolipid Storage Affects Autophagic Metabolism of the Amyloid Precursor Protein and Promotes Aβ Generation

Tamboli¹,

Hampel²,

Tiên³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

supporting

confidence: 93%

Sphingolipid Storage Affects Autophagic Metabolism of the Amyloid Precursor Protein and Promotes Aβ Generation

Tamboli¹,

Hampel²,

Tiên³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

“…Consistent with this hypothesis, increased molecular markers of autophagy have been reported in a number of LSDs such as Nieman-Pick type C (10, 11), multiple sulfatase deficiency (12), mucolipidosis Type IV (13-16), Pompe (17), Batten (18), and GM 1 gangliosidosis (19). In this study, we hypothesized that the apparent increase in protein turnover was due, in part, to an autophagic process that resulted from the deficiency of simple carbohydrates and lipids.…”

Section: Discussionmentioning

confidence: 53%

Metabolic Adaptations to Interrupted Glycosaminoglycan Recycling

Woloszynek

Kovács

Ohlemiller

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Lysosomal storage diseases (LSD) are metabolic disorders characterized by accumulation of undegraded material. The mucopolysaccharidoses (MPS) are LSDs defined by the storage of glycosaminoglycans. Previously, we hypothesized that cells affected with LSD have increased energy expenditure for biosynthesis because of deficiencies of raw materials sequestered within the lysosome. Thus, LSDs can be characterized as diseases of deficiency as well as overabundance (lysosomal storage). In this study, metabolite analysis identified deficiencies in simple sugars, nucleotides, and lipids in the livers of MPSI mice. In contrast, most amino acids, amino acid derivatives, dipeptides, and urea were elevated. These data suggest that protein catabolism, perhaps because of increased autophagy, is at least partially fulfilling intermediary metabolism. Thus, maintaining glycosaminoglycan synthesis in the absence of recycled precursors results in major shifts in the energy utilization of the cells. A high fat diet increased simple sugars and some fats and lowered the apparent protein catabolism. Interestingly, autophagy, which is increased in several LSDs, is responsive to dietary intervention and is reduced in MPSVII and MPSI mice fed a high fat diet. Although long term dietary treatment improved body weight in MPSVII mice, it failed to improve life span or retinal function. In addition, the ventricular hypertrophy and proximal aorta dilation observed in MPSVII mice were unchanged by a high fat, simple sugar diet. As the mechanism of this energy imbalance is better understood, a more targeted nutrient approach may yet prove beneficial as an adjunct therapy to traditional approaches. Lysosomal storage disease (LSD)2 typically results from a genetic deficiency of an acid hydrolase (1). The material usually degraded by the enzyme now accumulates in the lysosomes of cells throughout the body. In normal cells, some proportion of the degraded material is exported to the cytosol for reuse, thereby reducing the energy burden on the cell (2, 3). In the case of LSDs, more energy must be diverted to the synthesis of raw material because of the impaired recycling. Thus, this class of disorders presents with an energy imbalance caused by a simultaneous excess of stored material and a deficiency of raw material (4).Deficiencies in lysosomal enzymes involved in glycosaminoglycan (GAG) catabolism result in the mucopolysaccharidoses (MPS) (5). The biochemical, histological, and clinical phenotypes of MPS are likely due to a combination of the adaptations to both lysosomal storage and a deficiency of recycled monosaccharides. Maintaining a normal rate of GAG biosynthesis would require newly imported or synthesized monosaccharides, irrespective of the adaptations to stored material. The increased demand for GAG precursors is likely to be considerable. It has been shown previously in cultured cells that reutilization of catabolites from lysosomal GAG degradation is substantial (2). Therefore, the increased energy burden required for de novo synthesis...

show abstract

“…Accumulation of these storage compounds in ER membranes affects several functions of the organelle, (e.g., Ca 2þ homeostasis) (LaPlante et al 2002;Pelled et al 2003) and signaling cascades (Takamura et al 2008). …”

Section: Accumulation Of Sphingolipids In Cellular Membranes Outsidementioning

confidence: 99%