Motor Deficit in a Drosophila Model of Mucolipidosis Type IV due to Defective Clearance of Apoptotic Cells

Venkatachalam, Kartik; Long, A. Ashleigh; Elsaesser, Rebecca; Nikolaeva, Daria; Broadie, Kendal; Montell, Craig

doi:10.1016/j.cell.2008.09.041

Cited by 195 publications

(214 citation statements)

References 52 publications

(81 reference statements)

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“…We note that, unlike TPCs, evidence that TRPML1 functions as a Ca 2ϩ channel in the lysosomes or to participate in Ca 2ϩ release from other intracellular organelles is limited. However, TRPML1 has been shown to regulate lysosomal pH (23)(24)(25). Based on the available evidence, we thus suggest that TRPMLs and the TPCs may have different functions within the endo/lysosomal system.…”

Section: Discussionmentioning

confidence: 74%

See 1 more Smart Citation

Transient Receptor Potential Mucolipin 1 (TRPML1) and Two-pore Channels Are Functionally Independent Organellar Ion Channels

Yamaguchi

Jha

et al. 2011

Journal of Biological Chemistry

104

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NAADP is a potent second messenger that mobilizes Ca 2؉from acidic organelles such as endosomes and lysosomes. The molecular basis for Ca 2؉ release by NAADP, however, is uncertain. TRP mucolipins (TRPMLs) and two-pore channels (TPCs) are Ca 2؉ -permeable ion channels present within the endolysosomal system. Both have been proposed as targets for NAADP. In the present study, we probed possible physical and functional association of these ion channels. Exogenously expressed TRPML1 showed near complete colocalization with TPC2 and partial colocalization with TPC1. TRPML3 overlap with TPC2 was more modest. TRPML1 and to some extent TRPML3 co-immunoprecipitated with TPC2 but less so with TPC1. Current recording, however, showed that TPC1 and TPC2 did not affect the activity of wild-type TRPML1 or constitutively active TRPML1(V432P). N-terminally truncated TPC2 (TPC2delN), which is targeted to the plasma membrane, also failed to affect TRPML1 and TRPML1 ( ؊/؊ cells. We conclude that although TRPML1 and TPCs are present in the same complex, they function as two independent organellar ion channels and that TPCs, not TRPMLs, are the targets for NAADP. Ca2ϩ plays a major role in the function of intracellular organelles including biosynthesis and membrane trafficking (1, 2). Although the mechanism controlling Ca 2ϩ in the endoplasmic reticulum has been studied extensively, very little is known about Ca 2ϩ homeostasis by other organelles. Furthermore, although accumulating evidence indicates that acidic organelles such as endosomes and lysosomes are dynamic Ca 2ϩ stores, the molecular basis for Ca 2ϩ release from these so-called "acidic Ca 2ϩ stores" (3) is at present defined poorly. By far, the best characterized route for mobilization of acidic Ca 2ϩ stores is through the production of the potent Ca 2ϩ -releasing second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP) 5 (4). The Ca 2ϩ -mobilizing properties of NAADP were discovered in sea urchin eggs (5), in which NAADP was shown to mobilize Ca 2ϩ not from the endoplasmic reticulum but instead from lysosome-related organelles (6). Its effects have subsequently been extended to a variety of cell types, including pancreatic acinar and ␤ cells, smooth muscle cells, neurons, and breast cancer cells (4). NAADP is produced by several extracellular stimuli in an agonist-specific manner and implicated in a number of physiological responses, including fertilization, glucose sensing, exocytosis, and neuronal growth (4). Deregulated lysosomal Ca 2ϩ signaling may also result in disease (2,7,8). Despite the physiological and potential pathophysiological importance of NAADP signaling, the molecular identity of the NAADP receptor is not entirely clear (9). Recently, members of the transient receptor potential mucolipin (TRPML) (10, 11) and two-pore channel (TPC) (12-16) families, which are all present in the endo/lysosomal system, have been proposed as candidates.TRPMLs form a subfamily of the superfamily of the TRP channels. The founding member is TRPML1, which was ide...

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Section: Discussionmentioning

confidence: 74%

“…The function of TRPMLs is known to a limited extent. TRPML1 is expressed largely in late endosomes and lysosomes (19 -22), where it appears to regulate lysosomal pH (23)(24)(25). Deletion of TRPML1 in mammalian cells (24,26,27) and Caenorhabditis elegans (21,28) indicate that TRPML1 is required for membrane trafficking.…”

Section: Camentioning

confidence: 99%

Transient Receptor Potential Mucolipin 1 (TRPML1) and Two-pore Channels Are Functionally Independent Organellar Ion Channels

Yamaguchi

Jha

et al. 2011

Journal of Biological Chemistry

104

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“…These data suggest increased lysosomal storage as a result of an Atrophin-specific effect. Indeed, autofluorescent ageing pigments such as lipofuscin, a product of unsaturated fatty acid oxidation associated with several lysosomal pathologies, that can be visualised by autofluorescence at 488 nm, 30 accumulate in large vesicles in dissected single ommatidia that express Atro75QN (Figure 6b). Likewise, the Drosophila polyubiquitin-binding protein Ref (2)P/p62, 31 a multifunctional scaffold protein that marks ubiquitinated protein aggregates destined to degradation through the autophagic-lysosomal machinery, 32 accumulates in a number of small and large bodies upon wt Atro and, more conspicuously, upon polyQ Atro overexpression (Figure 6c).…”

Section: Resultsmentioning

confidence: 99%

“…30,34 We have generated new animal models for DRPLA in D. melanogaster. The DRPLA mouse models generated in the past 35,36 have been shown to recapitulate much of the human pathology but they are less flexible and genetically amenable than Drosophila, which has proved to be a valuable tool for dissecting the polyQ pathology.…”

Section: Discussionmentioning

confidence: 99%

Neurodegeneration by polyglutamine Atrophin is not rescued by induction of autophagy

et al. 2010

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Polyglutamine pathologies are neurodegenerative diseases that manifest both general polyglutamine toxicity and mutant protein-specific effects. Dentatorubral-pallidoluysian Atrophy (DRPLA) is one of these disorders caused by mutations in the Atrophin-1 protein. We have generated several models for DRPLA in Drosophila and analysed the mechanisms of cellular and organism toxicity. Our genetic and ultrastructural analysis of neurodegeneration suggests that autophagy may have a role in cellular degeneration when polyglutamine proteins are overexpressed in neuronal and glial cells. Clearance of autophagic organelles is blocked at the lysosomal level after correct fusion between autophagosomes and lysosomes. This leads to accumulation of autofluorescent pigments and proteinaceous residues usually degraded by the autophagy-lysosome system. Under these circumstances, further pharmacological and genetic induction of autophagy does not rescue neurodegeneration by polyglutamine Atrophins, in contrast to many other neurodegenerative conditions. Our data thus provide a crucial insight into the specific mechanism of a polyglutamine disease and reveal important differences in the role of autophagy with respect to other diseases of the same family. PolyQ-expanded proteins misfold and accumulate in large aggregates, which have been initially described as toxic, 1 and more recently as a positive prognosis factor in neuronal survival.2 The molecular and cellular mechanisms of toxicity due to polyQ proteins are not yet fully characterised and many of the principal aspects are under intense scrutiny. In particular, many reports have described autophagy as a protective cellular mechanism in neurodegeneration, 3 although its full contribution to the pathogenesis, including cell killing, is still poorly understood. The full cycle of autophagic degradation of cellular components and recycle of simpler constituents is not involved in cell killing. However, many dysfunctions at different steps of this cycle that have been reported upon expression of toxic proteins, including polyQ proteins, can lead to cell degeneration and death. 4 Over the past few years a growing number of studies have focused on identifying the interplay between polyQ effects and protein-specific misfunctions, 5-7 with the assumption that polyQ pathologies combine general polyQ toxicity with disease-specific effects due to the proteins affected. The fruitfly Drosophila melanogaster has proved to be a valuable model organism for polyQ diseases and neurodegeneration. New models have also moved on from initial basic observations, uncovering the complex interplay between polyQ effects and RNA or protein-specific misfunction. 5,7,9 We generated several Drosophila models of DRPLA ( Figure 1a and Supplementary Figure 1), a polyQ disease caused by mutations in atrophin-1.10,11 Atrophins are transcriptional cofactors conserved from Drosophila to mammals, 12-15 providing an ideal background for the dissection of polyQ effects and specific Atrophin functions through Drosophila ...

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“…To detect autophagosomes in situ, we expressed the following autophagosomal/autolysosomal markers in photoreceptor cells: GFP-conjugated Atg8b (GFP-Atg8b), Myc-tagged Atg1 (Atg1-Myc), and Myc-tagged Atg6 (Atg6-Myc) (Scott et al, 2004;Tekinay et al, 2006;Sun et al, 2008;Venkatachalam et al, 2008). Whereas only small punctate areas, positive for both GFPAtg8b and Atg1-Myc, were detected under dark-reared conditions, these double-positive structures were much larger after exposure to light (Fig.…”

Section: Autophagosomes Containing Rh1 Are Deformed By Psd Knockdownmentioning

confidence: 99%

Autophagy-Dependent Rhodopsin Degradation Prevents Retinal Degeneration inDrosophila

Midorikawa

Yamamoto-Hino²,

Awano³

et al. 2010

J. Neurosci.

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Recent studies have demonstrated protective roles for autophagy in various neurodegenerative disorders, including the polyglutamine diseases; however, the role of autophagy in retinal degeneration has remained unclear. Accumulation of activated rhodopsin in some Drosophila mutants leads to retinal degeneration, and although it is known that activated rhodopsin is degraded in endosomal pathways in normal photoreceptor cells, the contribution of autophagy to rhodopsin regulation has remained elusive. This study reveals that activated rhodopsin is degraded by autophagy in collaboration with endosomal pathways to prevent retinal degeneration. Lightdependent retinal degeneration in the Drosophila visual system is caused by the knockdown or mutation of autophagy-essential components, such as autophagy-related protein 7 and 8 (atg-7/atg-8), or genes essential for PE (phosphatidylethanolamine) biogenesis and autophagosome formation, including Phosphatidylserine decarboxylase (Psd) and CDP-ethanolamine:diacylglycerol ethanolaminephosphotransferase (Ept). The knockdown of atg-7/8 or Psd/Ept produced an increase in the amount of rhodopsin localized to Rab7-positive late endosomes. This rhodopsin accumulation, followed by retinal degeneration, was suppressed by overexpression of Rab7, which accelerated the endosomal degradation pathway. These results indicate a degree of cross talk between the autophagic and endosomal/lysosomal pathways. Importantly, a reduction in rhodopsin levels rescued Psd knockdown-induced retinal degeneration. Additionally, the Psd knockdown-induced retinal degeneration phenotype was enhanced by Ppt1 inactivation, which causes infantile neuronal ceroid lipofuscinosis, implying that autophagy plays a significant role in its pathogenesis. Collectively, the current data reveal that autophagy suppresses light-dependent retinal degeneration in collaboration with the endosomal degradation pathway and that rhodopsin is a key substrate for autophagic degradation in this context.

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Motor Deficit in a Drosophila Model of Mucolipidosis Type IV due to Defective Clearance of Apoptotic Cells

Cited by 195 publications

References 52 publications

Transient Receptor Potential Mucolipin 1 (TRPML1) and Two-pore Channels Are Functionally Independent Organellar Ion Channels

Transient Receptor Potential Mucolipin 1 (TRPML1) and Two-pore Channels Are Functionally Independent Organellar Ion Channels

Neurodegeneration by polyglutamine Atrophin is not rescued by induction of autophagy

Autophagy-Dependent Rhodopsin Degradation Prevents Retinal Degeneration inDrosophila

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