InteractiveFly: GeneBrief

Transient receptor potential cation channel, mucolipin ortholog: Biological Overview | References

BIOLOGICAL OVERVIEW

Disruption of the TRPML1 channel results in the neurodegenerative disorder mucolipidosis type IV (MLIV), a lysosomal storage disease with severe motor impairments. The mechanisms underlying MLIV are poorly understood and there is no treatment. This study reports a Drosophila MLIV model, which recapitulates the key disease features, including abnormal intracellular accumulation of macromolecules, motor defects and neurodegeneration. The basis for the buildup of macromolecules is defective autophagy, which results in oxidative stress and impaired synaptic transmission. Late-apoptotic cells accumulate in trpml mutant brains suggesting diminished cell clearance. The accumulation of late apoptotic cells and motor deficits are suppressed by expression of trpml⁺ in neurons, glia or hematopoietic cells. It is concluded that the neurodegeneration and motor defects result primarily from decreased clearance of apoptotic cells. Since hematopoietic cells in humans are involved in clearance of apoptotic cells, the results raise the possibility that bone marrow transplantation may limit the progression of MLIV (Venkatachalam, 2008).

The Transient Receptor Potential (TRP) channel superfamily participates in a remarkable diversity of processes in the nervous system. Nevertheless, the only neurodegenerative disease linked to a TRP channel is the early childhood disorder, mucolipidosis IV (MLIV). This highly debilitating autosomal recessive disease is characterized by severe motor deficits, mental retardation and neurodegeneration, including retinal degeneration (Bach, 2005). MLIV is a lysosomal storage disorder (LSD); one of ~40 LSDs, which together represent the most common cause of neurodegeneration during childhood (Cooper, 2003). As is typical of LSDs, cells from MLIV patients contain large vesicles and accumulate lysosomal storage components (Bach, 2005). Nevertheless, the underlying bases of the MLIV symptoms are not known and there is no effective treatment (Venkatachalam, 2008).

A key advance was the discovery that MLIV results from loss-of-function mutations in TRPML1 (Bargal, 2000; Bassi, 2000; Sun, 2000). TRPML1 appears to be widely expressed and consistent with the nature of MLIV, TRPML1 localizes to late endosomes and lysosomes (Manzoni, 2004). A C. elegans TRPML1 homolog, CUP-5, is also present in these organelles (Fares, 2001). Mutations in cup-5 result in maternal-effect lethality, excessive cell death and accumulation of large vacuoles (Hersh, 2002). However, a role for cup-5 in the nervous system has not been described. Recently, a mouse MLIV model has been developed, which recapitulates many features of the disorder (Venugopal, 2007). Nevertheless, many critical questions remain regarding the cause of the progressive motor defects, neurodegeneration and the mechanistic link to lysosomal dysfunction. Most importantly, no concept has emerged that offers potential for developing therapies for treating MLIV (Venkatachalam, 2008).

This study reports the development of Drosophila as an animal model for MLIV. It was found that trpml mutant flies exhibited a phenotype remarkably reminiscent of MLIV. Most importantly, insights into the cellular mechanism underlying the neurodegeneration and motor impairments are reported. These findings provide a conceptual framework for developing strategies for treating this neurodegenerative disease (Venkatachalam, 2008).

Impairments in autophagy are implicated in the pathophysiology of several neurodegenerative diseases (Klionsky, 2007). MLIV may also involve a perturbation in autophagy, as suggested by a pharmacological study using a tissue culture model (Jennings, 2006). This study found that trpml mutant cells display impaired autophagy in vivo. However, in contrast to other models of LSDs (Settembre, 2007), there does not appear to be a block in fusion between the lysosomes and autophagosomes in trpml cells. Rather, there appeared to be reduced macromolecular degradation in autolysosomes following fusion (Venkatachalam, 2008).

Recent in vitro studies suggest that mammalian TRPML1 is a proton-permeable channel that provides a proton leak pathway in the lysosomal membrane (Soyombo, 2006; Miedel, 2008). Therefore, in the absence of the channel, it is proposed that over-acidification of the lysosomal lumen impairs normal degradation in autolysosomes, since lysosomal proteases are intimately dependent on the normal lysosomal pH (Venkatachalam, 2008).

In addition to playing a cytoprotective role by promoting clearance of toxic macromolecules, autophagy is important for the turnover of entire organelles, including damaged mitochondrial with disrupted trans-membrane potential (ΔΨ) (Twig, 2008). trpml neurons accumulate mitochondria with dissipated ΔΨ, indicating disruption of autophagic clearance of dysfunctional mitochondria. Moreover, trpml cells accumulate lipofuscin, indicative of oxidative stress, and the mutant animals display a significant increase in H₂O₂ in a range that leads to elevated apoptosis and neurodegeneration. Thus, oxidative stress appears to be a key factor contributing to the neurodegeneration in the trpml mutant (Venkatachalam, 2008).

To cope with oxidative stress and toxic aggregation of macromolecules, cells increase expression of molecular chaperones such as heat-shock proteins. Exogenous expression of the human homolog of HSP70 (HspA1L) can suppress the toxicity associated with HttQ120. Similarly, introduction of HspA1L into trpml neurons, but not in other cell types, rescues the mutant phenotypes. This finding indicates that the impairments in trpml arise primarily in neurons and possibly due to an accumulation of macromolecules (Venkatachalam, 2008).

Loss of TRPML causes a decrease in lysosomal degradation, resulting in an increase in dysfunctional mitochondrial, aggregation of toxic macromolecules and oxidative stress. Lipofuscin, which forms under oxidative stress (Terman, 2004), can cause a further decrease in lysosomal function. It is proposed that in trpml mutants there is an amplifying cycle of increased oxidative stress and defective autophagy and lysosomal function, which leads to progressive neurodegeneration and motor impairment. It is suggested that elevated oxidative stress also underlies the reduced NMJ synaptic transmission in trpml animals, which in turn contributes to the deficit in behavioral motor function. Consistent with this model, increased oxidative stress is linked to inhibition of synaptic transmission (Giniatullin, 2006). These results raise the possibility that a combination of neurodegeneration and loss of NMJ synaptic transmission accounts for the diminished motor activity in MLIV patients. Although it cannot be ruled out that the impaired synaptic transmission in trpml is an indirect consequence of unhealthy neurons, it still provides an explanation for the impaired motor function that precedes neurodegeneration in MLIV (Venkatachalam, 2008).

The trpml phenotype is reminiscent of the spinster/benchwarmer Drosophila mutant. Similarities include accumulation of lipofuscin-loaded effete lysosomes, loss of NMJ synaptic function and neurodegeneration. The Spinster/Benchwarmer protein also resides in a presynaptic lysosomal compartment and is implicated in efficient synaptic vesicle recycling (Venkatachalam, 2008).

Initially as a control, the wild-type trpml⁺ transgene was introduced in glia and fat-bodies/hemocytes and to surprisingly expression of trpml⁺ in these cells rescued the trpml mutant phenotypes. Thus, the issue arises as to why expression of TRPML in hematopoietic cells or glia rescues the trpml defects. Clarifying this mechanism may have relevance to other LSD models of progressive neurodegeneration (Venkatachalam, 2008).

Neural tissue in trpml animals accumulates early- and late-apoptotic/necrotic cells. Normally, early apoptotic cells are rapidly cleared by hemocytes and glia (Wood, 2007). If dead cells are not cleared rapidly, they lose plasma membrane integrity and release antigenic and cytotoxic material, which induce neuroinflammation and secondary necrosis in neighboring bystander cells. Loss of trpml function in neurons induces cell-autonomous apoptosis and defective clearance of these cells induces secondary cell death in nearby cells. Consistent with this proposal, introduction of trpml⁺ in neurons prevents cell death of both neurons and glia, indicating that trpml functions cell-autonomously for neuronal viability and non-autonomously for the viability of adjacent cells such as glia. When trpml was introduced in hemocytes or glia there was no accumulation of late-apoptotic cells or necrotic cells, although mutant cells still underwent early apoptosis (Venkatachalam, 2008).

It is suggested that expression of trpml⁺ in hemocytes and glia promotes the clearance of early apoptotic cells before their membrane integrity is compromised. In the absence of this function, there is an accumulation of late apoptotic/necrotic cells, leading to widespread neuroinflammation and progressive cell death in adjoining cells that would otherwise remain unaffected (Venkatachalam, 2008).

Since both late apoptotic/necrotic neurons and oxidative stress are mediators of neuroinflammation (Franc, 2002), the current results raise the possibility that neuroinflammation may be a hitherto unexplored mediator of MLIV associated neurodegeneration. This is the first link between a TRP channel and either neuroinflammation or clearance of apoptotic cells (Venkatachalam, 2008).

The finding that expression of wild-type trpml⁺ in hematopoietic cells is sufficient to delay the onset of the trpml mutant phenotypes raises the exciting possibility that bone marrow transplantation (BMT) in patients with MLIV might delay disease progression. In favor of this proposal, several reports and case studies describe the successful use of BMT to ameliorate other LSDs in patients and in murine models. With the recent development of TRPML1 knockout mice (Venugopal, 2007), the feasibility of this approach can now be tested in a mammalian animal model. The current results also raise the possibility that one or more of the approved drugs that stimulate either autophagy or HSP1AL may also suppress MLIV, especially in combination with BMT. Thus, this Drosophila model for MLIV provides the framework for developing strategies to treat MLIV (Venkatachalam, 2008).

Drosophila TRPML is required for TORC1 activation

Loss-of-function mutations in TRPML1 (transient receptor potential mucolipin 1) cause the lysosomal storage disorder, mucolipidosis type IV (MLIV). This study reports that flies lacking the TRPML1 homolog display incomplete autophagy and reduced viability during the pupal period -- a phase when animals rely on autophagy for nutrients. TRPML is required for fusion of amphisomes with lysosomes, and its absence leads to accumulation of vesicles of significantly larger volume and higher luminal Ca²⁺. It was also found that trpml¹ mutant cells showed decreased TORC1 (target of rapamycin complex 1) signaling and a concomitant upregulation of autophagy induction. Both of these defects in the mutants are reversed by genetically activating TORC1 or by feeding the larvae a high-protein diet. The high-protein diet also reduces the pupal lethality and the increased volume of acidic vesicles. Conversely, further inhibition of TORC1 activity by rapamycin exacerbates the mutant phenotypes. Finally, TORC1 exerts reciprocal control on TRPML function. A high-protein diet causes cortical localization of TRPML, and this effect is blocked by rapamycin. These findings delineate the interrelationship between the TRPML and TORC1 pathways and raise the intriguing possibility that a high-protein diet might reduce the severity of MLIV (Wong, 2012).

Drosophila transient receptor potential mucolipin (TRPML) localizes to late endosomes (LEs)/lysosomes in cultured cells (Venkatachalam, 2008). To identify the subcellular localization of TRPML in vivo, a UAS-trpml::myc transgene was expressed in flies using the GAL4/UAS system. TRPML::MYC decorated the periphery of LysoTracker-positive vesicles and colocalized with the LE/lysosomal markers YFP::Rab7 and lysosome-associated membrane protein:green fluorescent protein (LAMP::GFP). These data indicate that TRPML::MYC is a LE/lysosomal membrane protein, as is the case for mammalian TRPML1 (Venkatachalam, 2006; Wong, 2012 and references therein).

The trpml¹ flies are unable to complete lysosomal degradation of autophagosomes. To identify the step in the lysosomal degradation pathway affected in trpml¹, the degradation of the Drosophila Wnt homolog, Wingless (Wg) was evaluated. Following binding to its receptor, Wg is internalized into endosomes and degraded in lysosomes. It was found that there was increased accumulation of Wg in the wing pouch and notum of trpml¹ wing discs, and this phenotype was rescued by a trpml⁺ genomic transgene (P[trpml⁺];trpml¹) (Wong, 2012).

Wg could be accumulating either in early endosomes or in LEs/multivesicular bodies (MVBs) in trpml¹ discs. To discriminate between these possibilities, the observation was taken into account that Wg transmits signals at both the plasma membrane (PM) and early endosomes. Only after the formation of MVBs is the signal terminated. Therefore, increased Wg signaling in trpml¹ would suggest that Wg is accumulating in early endosomes, whereas unchanged Wg signaling would be consistent with Wg accumulating in MVBs. Therefore, activation of the Wg target gene Hindsight (Hnt) in wing discs was evaluated. Nuclear Hnt expression was indistinguishable between wild-type (WT) and trpml¹, indicating that Wg signaling was not increased in trpml¹ (Wong, 2012).

Accumulation of Notch was also evaluated using an antibody specific for the endocytosed domain of Notch, and it was found that levels of Notch increased dramatically in trpml¹ wing discs. Notch levels appeared higher than Wg in trpml¹ because whereas Wg accumulated in the wing pouch and notum, Notch was elevated over the whole disc. In support of the conclusion that the vesicles that accumulated in trpml¹ were LEs, the Notch-positive vesicles costained with LysoTracker (Wong, 2012).

Autophagy is a pathway required for the degradation of cellular macromolecules that are too big to fit through the proteosomal barrel. During autophagy, double-membrane-bound vesicles called autophagosomes isolate the cytosolic material destined for degradation. Subsequently, autophagosomes fuse with LEs/MVBs to form amphisomes. Amphisomes then coalesce with lysosomes leading to the formation of autolysosomes. Because lysosomes carry degradatory enzymes, the contents of amphisomes are broken down following autolysosome formation (Wong, 2012).

It has previously been reported that trpml¹ adults display hallmarks of decreased autophagic flux (Venkatachalam, 2008). To provide evidence that there was accumulation of autophagosome and amphisomes, WT and trpml¹ fat bodies were stained with LysoTracker and GFP::ATG8. Autophagosomes are labeled with GFP::ATG8 only, whereas amphisomes are stained with both GFP::ATG8 and LysoTracker. Although WT showed virtually no GFP::ATG8 staining, there were many trpml¹ vesicles that were labeled with GFP::ATG8 only or both GFP::ATG8 and LysoTracker. These data indicated that loss of trpml led to an elevation of autophagosomes and amphisomes. Defects in receptor degradation have also been reported in human cells lacking TRPML1 and in C. elegans with a mutation disrupting the worm TRPML1 homolog. These trpml¹ phenotypes closely resemble those of flies lacking fab1 (vesicular phosphatidylinositol 3-phosphate 5-kinase). These phenotypic similarities are consistent with the finding that the mammalian TRPML1 is activated by the product of Fab1/PIK-FYVE-kinase, PI(3,5)P(2) (Wong, 2012).

The sizes of LysoTracker-positive vesicles were compared in WT and trpml¹ larval fat bodies to assess autophagy induction. Consistent with increased induction of autophagy in trpml¹, there was a striking elevation in the volume of LysoTracker-positive vesicles in mutant fat bodies. This change became evident and was most pronounced in fat bodies from second-instar larvae. The difference between WT and trpml¹ was less pronounced but still significant in third-instar larvae. The smaller elevation in trpml¹ third-instar larvae likely reflects ecdysone-dependent autophagy activation in WT tissues at this developmental stage (Wong, 2012).

It was hypothesized that induction of autophagy without its completion should suppress target of rapamycin complex 1 (TORC1) activity due to two factors. First, a decline in autophagic flux would decrease net availability of amino acids that are produced via autophagic degradation of proteins. Reduced amino acid levels would diminish activity of the TORC1. Indeed, diminished autophagic flux by Atg7 knockdown led to reduced TORC1 activity as determined by phosphorylation of the TORC1 substrate, S6 kinase (pS6K). This study found a similar decrease in TORC1 activity after knocking down Atg5 in WT fat bodies using RNAi. Second, increased autophagy will directly suppress TORC1 function because autophagy and TORC1 activity are mutually antagonistic. Decreased TORC1 will induce further induction of autophagy leading to the generation of larger LysoTracker-positive vesicles (Wong, 2012).

Several lines of evidence support the preceding proposal. First, feeding trpml¹ third-instar larvae protein-rich yeast paste suppressed the increase in the volume of LysoTracker-positive vesicles. Second, pS6K was diminished in trpml¹ fat bodies. The decrease in pS6K in trpml¹ was reversed by driving WT trpml⁺ in fat bodies using cg-GAL4. Furthermore, yeast feeding suppressed the reduction in pS6K levels in trpml¹. To investigate whether decreased TORC1 activity occurs in other mutants with diminished fusion of LEs with lysosomes, pS6K was evaluated in dor mutants. Extracts from dor⁴ mutant larvae showed a reduction. Therefore, a block in the fusion of LEs with lysosomes results in decreased cellular amino acid levels and decreased TORC1 activity (Wong, 2012).

Third, genetically upregulating TORC1 activity in mutant fat bodies by overexpressing Rheb and constitutively active Rag (Rag^Q61L) (Kim, 2008) decreased the LysoTracker-positive vesicular volume. Vesicular volume in trpml¹ did not increase any further when dominant-negative Rag (Rag^T16N) was expressed, indicating that Rag activity was already maximally reduced in trpml¹. The finding that elevating TORC1 activity is sufficient to suppress lysosomal storage argues that the increase in acidic vesicles in trpml¹ reflects a decrease in TORC1 activity. Therefore, elevating TORC1 activity is sufficient to prevent vesicle accumulation despite the persistence of vesicle fusion defects (Wong, 2012).

Finally, the half-maximal time to pupation was increased in trpml¹. Because decreased TORC1 activity causes a developmental delay, these data are also consistent with a decrease in TORC1 activity in trpml¹. Feeding the larvae protein-rich yeast paste restored pS6K levels to WT and rescued the defect in developmental timing (Wong, 2012).

Late endosome/lysosomal Ca²⁺ is required for the homotypic and heterotypic fusion of these vesicles. Therefore, the increased LysoTracker staining in trpml¹ may have resulted from diminished Ca²⁺ release from the vesicles leading to impaired fusion of the early endosome/amphisomes with lysosomes, ultimately resulting in reduced degradation of their contents. Consistent with the proposal that increased vesicular volume stemmed from diminished Ca²⁺ release, treatment of the fat bodies with thapsigargin, which blocks the sarcoplasmic/endoplasmic reticulum calcium ATPase pump and causes Ca²⁺ release from endoplasmic reticulum stores, resulted in a significant decrease in the volume of LysoTracker-positive vesicles in trpml¹. Therefore, despite the absence of a late endosome Ca²⁺ release mechanism in trpml¹, elevation of cytosolic Ca²⁺ levels from a different Ca²⁺ reserve was sufficient to partially suppress the increase in LysoTracker-positive vesicle volume. Although the data are most consistent with a defect in the fusion of vesicles in trpml¹, it cannot be ruled out that there may also be a defect in vesicular trafficking, thereby reducing encounters between fusible vesicles (Wong, 2012).

During the pupal period Drosophila do not feed, and they depend on autophagy for the amino acids necessary for morphogenesis and survival. Loss of trpml causes semilethality during the pupal period because <10% of adults eclose from the pupal cases (Venkatachalam, 2008). To test whether this reduced viability resulted from an insufficient supply of amino acids, the mutant larvae were fed a high-protein diet (food supplemented with 20% w/v yeast). It was found that this diet significantly suppressed the lethality. However, the effects of another mutation that caused pupal lethality (P element inserted in vamp-7, CG1599^EY09354) were not suppressed by yeast supplementation (Wong, 2012).

The suppression of the trpml semilethality by yeast paste could have been due to either protein or carbohydrates in this supplement. Therefore, whether supplementation of either tryptone or sucrose diminished the lethality was tested. It was found that whereas tryptone supplementation reduced the semilethality, sucrose supplementation did not. The lack of suppression with sucrose indicated that the phenotype was not a result of caloric deprivation but rather reflected a requirement for increased dietary amino acids by trpml¹ larvae (Wong, 2012).

Next, whether the suppression of the semilethality by the high-protein diet was due to increased TORC1 activity was considered. Yeast paste was fed to trpml¹ larvae in the presence of the TORC1 inhibitor, rapamycin. It was found that rapamycin prevented suppression of the pupal semilethality by yeast paste. Moreover, rapamycin enhanced the lethality when trpml¹ larvae were reared on normal food. However, feeding the dor mutants rapamycin did not decrease their viability. These data indicate that not all mutants with deficient fusion of LEs to lysosomes show increased sensitivity to rapamycin (Wong, 2012).

TORC1 simultaneously increases protein translation and decreases autophagy. One of the ways through which TORC1 increases protein translation is phosphorylation and inhibition of the translational suppressor Thor -- fly homolog of 4E-BP1. Therefore, if the effects of TORC1 activation in trpml¹ depend upon protein translation, then rapamycin should not reverse the beneficial effect of yeast feeding in thor²;trpml¹ double-mutant animals. However, yeast paste still suppressed the semilethality in thor²;trpml¹ double mutants (no thor²;trpml¹ adults eclosed in the absence of yeast-supplemented diet), and the effect of rapamycin remained unchanged. These results suggest that activation of TORC1 by high levels of amino acids may have suppressed the pupal semilethality of trpml¹ by decreasing autophagy rather than by increasing protein translation (Wong, 2012).

To investigate whether TORC1 activity reciprocally affected TRPML, the spatial distribution was examined of TRPML::MYC under conditions in which TORC1 activity was manipulated. On a normal diet, TRPML::MYC was exclusively intracellular. However, on a high-protein diet, TRPML::MYC colocalized with the cortical F-actin marker phalloidin, indicating that TRPML was at the plasma membrane. In larvae maintained on a high-protein diet and rapamycin, TRPML::MYC was detected exclusively in intracellular vesicles. These data indicate that the PM localization of TRPML::MYC depends on the activity of TORC1. Further supporting this conclusion, TRPML::MYC was predominantly localized to the PM in larval salivary glands, which are characterized by low levels of autophagy (and therefore high TORC1 activity) until the onset of the pupal phase, when autophagy is required for the degradation of the pupal salivary gland during metamorphosis (Wong, 2012).

The effect of TORC1 activity on the subcellular location of TRPML is unlikely to reflect alterations in bulk endocytosis because TORC1 enhances rather than suppresses bulk endocytosis. Rather, it is suggested that by occluding entry of TRPML into endosomes and diminishing the levels of TRPML in the late endosomes, TORC1 exerts feedback regulation on the completion of autophagy. Therefore, in addition to suppressing the initiation of autophagy, TORC1 also inhibits the completion of autophagy by regulating the subcellular location of TRPML (Wong, 2012).

TRPML is a Ca²⁺ channel, which is endocytosed from the PM and eventually enters the late endosomes (LEs). The LEs fuse with autophagosomes creating amphisomes. TRPML present in amphisomes releases luminal Ca²⁺ to facilitate Ca²⁺-dependent fusion of amphisomes with lysosomes. The amino acids generated by degradation of proteins in the autolysosomes promote TORC1 activation. In addition to inhibiting the initiation of autophagy, activated TORC1 also diminishes endocytosis of TRPML (Wong, 2012).

In the absence of TRPML, fusion of amphisomes and lysosomes is impaired. This leads to a decrease in autophagic flux of amino acids causing a reduction in TORC1 and upregulation of autophagy. Supplementing the trpml¹ diet with protein-rich yeast reverses the effects of diminished TORC1 activity. These findings raise the possibility that patients with mucolipidosis type IV (MLIV) may also show diminished TORC1 activity. If so, it is intriguing to speculate that amino acid supplementation might reduce the severity of the clinical manifestations associated with MLIV (Wong, 2012).

Feast or famine: role of TRPML in preventing cellular amino acid starvation

Lysosomal storage diseases are metabolic disorders characterized by the accumulation of acidic vacuoles, and are usually the consequence of the deficiency of an enzyme responsible for the metabolism of vesicular lipids, proteins or carbohydrates. In contrast, mucolipidosis type IV (MLIV), results from the absence of a vesicular Ca ²⁺ release channel called mucolipin 1/transient receptor potential mucolipin 1 (MCOLN1/TRPML1) which is required for the fusion of amphisomes with lysosomes. In Drosophila, ablation of the MCOLN1 homolog (trpml) leads to diminished viability during pupation when the animals rely on autophagy for nutrients. This pupal lethality results from decreased target of rapamycin complex 1 (TORC1) signaling, and is reversed by reactivating TORC1. These findings indicate that one of the primary causes of toxicity in the absence of TRPML is cellular amino acid starvation, and the resulting decrease in TORC1 activity. Furthermore, these findings raise the intriguing possibility that the neurological dysfunction in MLIV patients may arise from amino acid deprivation in neurons. Therefore, future studies evaluating the levels of amino acids and TORC1 activity in MLIV neurons may aid in the development of novel therapeutic strategies to combat the severe manifestations of MLIV (Venkatachalam, 2013).

Search PubMed for articles about Trpml

Bach, G. (2005). Mucolipin 1: endocytosis and cation channel--a review. Pflugers Arch 451: 313-317. PubMed ID: 15570434

Bargal, R., Avidan, N., Ben-Asher, E., Olender, Z., Zeigler, M., Frumkin, A., Raas-Rothschild, A., Glusman, G., Lancet, D. and Bach, G. (2000). Identification of the gene causing mucolipidosis type IV. Nat Genet 26: 118-123. PubMed ID: 10973263

Bassi, M. T., Manzoni, M., Monti, E., Pizzo, M. T., Ballabio, A. and Borsani, G. (2000). Cloning of the gene encoding a novel integral membrane protein, mucolipidin-and identification of the two major founder mutations causing mucolipidosis type IV. Am J Hum Genet 67: 1110-1120. PubMed ID: 11013137

Cooper, J. D. (2003). Progress towards understanding the neurobiology of Batten disease or neuronal ceroid lipofuscinosis. Curr Opin Neurol 16: 121-128. PubMed ID: 12644737

Fares, H. and Greenwald, I. (2001). Regulation of endocytosis by CUP-5, the Caenorhabditis elegans mucolipin-1 homolog. Nat Genet 28: 64-68. PubMed ID: 11326278

Franc, N. C. (2002). Phagocytosis of apoptotic cells in mammals, caenorhabditis elegans and Drosophila melanogaster: molecular mechanisms and physiological consequences. Front. Biosci. 7: d1298-d1313.

Giniatullin, A. R., Darios, F., Shakirzyanova, A., Davletov, B. and Giniatullin, R. (2006). SNAP25 is a pre-synaptic target for the depressant action of reactive oxygen species on transmitter release. J Neurochem 98: 1789-1797. PubMed ID: 16945102

Hersh, B. M., Hartwieg, E. and Horvitz, H. R. (2002). The Caenorhabditis elegans mucolipin-like gene cup-5 is essential for viability and regulates lysosomes in multiple cell types. Proc Natl Acad Sci U S A 99: 4355-4360. PubMed ID: 11904372

Jennings, J. J., Jr., Zhu, J. H., Rbaibi, Y., Luo, X., Chu, C. T. and Kiselyov, K. (2006). Mitochondrial aberrations in mucolipidosis Type IV. J Biol Chem 281: 39041-39050. PubMed ID: 17056595

Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P. and Guan, K. L. (2008). Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10: 935-945. PubMed ID: 18604198

Klionsky, D. J. (2007). Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8: 931-937. PubMed ID: 17712358

Manzoni, M., Monti, E., Bresciani, R., Bozzato, A., Barlati, S., Bassi, M. T. and Borsani, G. (2004). Overexpression of wild-type and mutant mucolipin proteins in mammalian cells: effects on the late endocytic compartment organization. FEBS Lett 567: 219-224. PubMed ID: 15178326

Miedel, M. T., Rbaibi, Y., Guerriero, C. J., Colletti, G., Weixel, K. M., Weisz, O. A. and Kiselyov, K. (2008). Membrane traffic and turnover in TRP-ML1-deficient cells: a revised model for mucolipidosis type IV pathogenesis. J Exp Med 205: 1477-1490. PubMed ID: 18504305

Settembre, C., Fraldi, A., Rubinsztein, D. C. and Ballabio, A. (2008). Lysosomal storage diseases as disorders of autophagy. Autophagy 4: 113-114. PubMed ID: 18000397

Soyombo, A. A., Tjon-Kon-Sang, S., Rbaibi, Y., Bashllari, E., Bisceglia, J., Muallem, S. and Kiselyov, K. (2006). TRP-ML1 regulates lysosomal pH and acidic lysosomal lipid hydrolytic activity. J Biol Chem 281: 7294-7301. PubMed ID: 16361256

Sun, M., Goldin, E., Stahl, S., Falardeau, J. L., Kennedy, J. C., Acierno, J. S., Jr., Bove, C., Kaneski, C. R., Nagle, J., Bromley, M. C., Colman, M., Schiffmann, R. and Slaugenhaupt, S. A. (2000). Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum Mol Genet 9: 2471-2478. PubMed ID: 11030752

Terman, A., Brunk, U. T. (2004). Lipofuscin. Int. J. Biochem. Cell Biol. 36: 1400-1404. PubMed ID: 15147719

Twig, G., Elorza, A., Molina, A. J., Mohamed, H., Wikstrom, J. D., Walzer, G., Stiles, L., Haigh, S. E., Katz, S., Las, G., Alroy, J., Wu, M., Py, B. F., Yuan, J., Deeney, J. T., Corkey, B. E. and Shirihai, O. S. (2008). Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27: 433-446. PubMed ID: 18200046

Venugopal, B., Browning, M. F., Curcio-Morelli, C., Varro, A., Michaud, N., Nanthakumar, N., Walkley, S. U., Pickel, J. and Slaugenhaupt, S. A. (2007). Neurologic, gastric, and opthalmologic pathologies in a murine model of mucolipidosis type IV. Am J Hum Genet 81: 1070-1083. PubMed ID: 17924347

Venkatachalam, K., Long, A. A., Elsaesser, R., Nikolaeva, D., Broadie, K. and Montell, C. (2008). Motor deficit in a Drosophila model of mucolipidosis type IV due to defective clearance of apoptotic cells. Cell 135: 838-851. PubMed ID: 19041749

Venkatachalam, K., Wong, C. O. and Montell, C. (2013). Feast or famine: role of TRPML in preventing cellular amino acid starvation. Autophagy 9: 98-100. PubMed ID: 23047439

Wood, W. and Jacinto, A. (2007). Drosophila melanogaster embryonic haemocytes: masters of multitasking. Nat Rev Mol Cell Biol 8: 542-551. PubMed ID: 17565363

Wong, C. O., Li, R., Montell, C. and Venkatachalam, K. (2012). Drosophila TRPML is required for TORC1 activation. Curr Biol 22: 1616-1621. PubMed ID: 22863314

date revised: 30 May 2013

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