Cell death pathways in juvenile Batten disease

Persaud-Sawin, Dixie-Ann; Boustany, Rose‐Mary

doi:10.1007/s10495-005-0733-6

Cited by 45 publications

(62 citation statements)

References 99 publications

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“…9), since further up-regulation of autophagy fails to significantly impact cell survival, but inhibition of autophagy leads to cell death, most likely by apoptotic mechanisms (35,40). mTOR-mediated autophagy is known to be stimulated by cellular stress, energy depletion, and nutrient deprivation (2).…”

Section: Discussionmentioning

confidence: 99%

Autophagy Is Disrupted in a Knock-in Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis

Cao

Espinola

Fossale

et al. 2006

Journal of Biological Chemistry

232

222

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Juvenile neuronal ceroid lipofuscinosis is caused by mutation of a novel, endosomal/lysosomal membrane protein encoded by CLN3. The observation that the mitochondrial ATPase subunit c protein accumulates in this disease suggests that autophagy, a pathway that regulates mitochondrial turnover, may be disrupted. To test this hypothesis, we examined the autophagic pathway in Cln3 ⌬ex7/8 knock-in mice and CbCln3 ⌬ex7/8 cerebellar cells, accurate genetic models of juvenile neuronal ceroid lipofuscinosis. In homozygous knock-in mice, we found that the autophagy marker LC3-II was increased, and mammalian target of rapamycin was down-regulated. Moreover, isolated autophagic vacuoles and lysosomes from homozygous knock-in mice were less mature in their ultrastructural morphology than the wild-type organelles, and subunit c accumulated in autophagic vacuoles. Intriguingly, we also observed subunit c accumulation in autophagic vacuoles in normal aging mice. Upon further investigation of the autophagic pathway in homozygous knock-in cerebellar cells, we found that LC3-positive vesicles were altered and overlap of endocytic and lysosomal dyes was reduced when autophagy was stimulated, compared with wildtype cells. Surprisingly, however, stimulation of autophagy did not significantly impact cell survival, but inhibition of autophagy led to cell death. Together these observations suggest that autophagy is disrupted in juvenile neuronal ceroid lipofuscinosis, likely at the level of autophagic vacuolar maturation, and that activation of autophagy may be a prosurvival feedback response in the disease process.Macroautophagy (herein referred to as autophagy) is a nonselective process by which cytoplasmic constituents are turned over (reviewed in Refs. 1 and 2). Elegant work in yeast has led to the genetic dissection of many of the proteins involved in this pathway (3, 4), which are mostly conserved in mammals (5, 6).The pathway is initiated at times of stress or nutritional deprivation to generate metabolites for cellular survival, but autophagy is also responsible for normal housekeeping. Although the regulatory control of autophagy remains to be fully elucidated, the general process from engulfment to degradation has been delineated (2). Initiation of the pathway involves de novo formation of an isolation membrane that expands to engulf cytoplasmic constituents, including organelles, and encloses to form a double membrane autophagic vacuole. This formed autophagic vacuole is then increasingly acidified, and proteases are delivered through fusion with late endosomes and lysosomes. The inner membrane is degraded to form a single membrane autolysosome, where constituents are finally completely degraded for recycling of metabolites to the cell.Autophagy is emerging as a major pathway involved in a number of neurodegenerative diseases, including Parkinson disease (7, 8), Huntington disease (9 -11), and Alzheimer disease (12, 13). In each case, autophagic vacuoles accumulate, suggesting that activation of autophagy is a common feature ...

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Section: Discussionmentioning

confidence: 99%

Autophagy Is Disrupted in a Knock-in Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis

Cao

Espinola

Fossale

et al. 2006

Journal of Biological Chemistry

232

222

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“…Autophagosome-rich forms of cell death elicited by other stimuli have also been reported to occur through caspase-8 rather than caspase-9-dependent pathways (67,68). Although the term autophagic cell death or type II programmed cell death has been used to describe this morphology, it is controversial whether the increased autophagy contributes to cell death or represents a failed compensatory reaction (20 -22, 69, 70).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Aberrations in Mucolipidosis Type IV

Jennings

Zhu

Rbaibi

et al. 2006

Journal of Biological Chemistry

138

124

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Mucolipidosis type IV is a genetic lysosomal storage disease associated with degenerative processes in the brain, eye, and other tissues. Mucolipidosis type IV results from mutations in the gene MCOLN1, which codes for the TRP family ion channel, mucolipin 1. The connection between lysosomal dysfunction and degenerative processes in mucolipidosis type IV is unclear. Here we report that mucolipidosis type IV and several unrelated lysosomal storage diseases are associated with significant mitochondrial fragmentation and decreased mitochondrial Ca

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“…Prenylated CLN3p promotes association to LRs (21). These house caspase-8 activated in apoptotic CLN3-deficient cells (22). It has been suggested CLN3p contributes to [Delta]-9 desaturase activity, which targets LR-associated palmitoylated proteins (23).…”

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confidence: 99%