Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue!
Lysosomal storage diseases (LSDs) resulting from inherited gene mutations constitute a family of disorders that disturb lysosomal degradative function leading to abnormal storage of macromolecular substrates. In most LSDs, central nervous system (CNS) involvement is common and leads to the progressi...
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MDPI AG
2022-09-01
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| Series: | Cells |
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| author | Sandra Prat Castro Veronika Kudrina Dawid Jaślan Julia Böck Anna Scotto Rosato Christian Grimm |
| author_facet | Sandra Prat Castro Veronika Kudrina Dawid Jaślan Julia Böck Anna Scotto Rosato Christian Grimm |
| author_sort | Sandra Prat Castro |
| collection | DOAJ |
| description | Lysosomal storage diseases (LSDs) resulting from inherited gene mutations constitute a family of disorders that disturb lysosomal degradative function leading to abnormal storage of macromolecular substrates. In most LSDs, central nervous system (CNS) involvement is common and leads to the progressive appearance of neurodegeneration and early death. A growing amount of evidence suggests that ion channels in the endolysosomal system play a crucial role in the pathology of neurodegenerative LSDs. One of the main basic mechanisms through which the endolysosomal ion channels regulate the function of the endolysosomal system is Ca<sup>2+</sup> release, which is thought to be essential for intracellular compartment fusion, fission, trafficking and lysosomal exocytosis. The intracellular TRPML (transient receptor potential mucolipin) and TPC (two-pore channel) ion channel families constitute the main essential Ca<sup>2+</sup>-permeable channels expressed on endolysosomal membranes, and they are considered potential drug targets for the prevention and treatment of LSDs. Although TRPML1 activation has shown rescue effects on LSD phenotypes, its activity is pH dependent, and it is blocked by sphingomyelin accumulation, which is characteristic of some LSDs. In contrast, TPC2 activation is pH-independent and not blocked by sphingomyelin, potentially representing an advantage over TRPML1. Here, we discuss the rescue of cellular phenotypes associated with LSDs such as cholesterol and lactosylceramide (LacCer) accumulation or ultrastructural changes seen by electron microscopy, mediated by the small molecule agonist of TPC2, TPC2-A1-P, which promotes lysosomal exocytosis and autophagy. In summary, new data suggest that TPC2 is a promising target for the treatment of different types of LSDs such as MLIV, NPC1, and Batten disease, both in vitro and in vivo. |
| first_indexed | 2024-03-10T00:26:54Z |
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| language | English |
| last_indexed | 2024-03-10T00:26:54Z |
| publishDate | 2022-09-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-ac7d56d7ef93495b92dc1559072b68092023-11-23T15:32:33ZengMDPI AGCells2073-44092022-09-011118280710.3390/cells11182807Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue!Sandra Prat Castro0Veronika Kudrina1Dawid Jaślan2Julia Böck3Anna Scotto Rosato4Christian Grimm5Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, 80336 Munich, GermanyWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, 80336 Munich, GermanyWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, 80336 Munich, GermanyWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, 80336 Munich, GermanyWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, 80336 Munich, GermanyWalther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, 80336 Munich, GermanyLysosomal storage diseases (LSDs) resulting from inherited gene mutations constitute a family of disorders that disturb lysosomal degradative function leading to abnormal storage of macromolecular substrates. In most LSDs, central nervous system (CNS) involvement is common and leads to the progressive appearance of neurodegeneration and early death. A growing amount of evidence suggests that ion channels in the endolysosomal system play a crucial role in the pathology of neurodegenerative LSDs. One of the main basic mechanisms through which the endolysosomal ion channels regulate the function of the endolysosomal system is Ca<sup>2+</sup> release, which is thought to be essential for intracellular compartment fusion, fission, trafficking and lysosomal exocytosis. The intracellular TRPML (transient receptor potential mucolipin) and TPC (two-pore channel) ion channel families constitute the main essential Ca<sup>2+</sup>-permeable channels expressed on endolysosomal membranes, and they are considered potential drug targets for the prevention and treatment of LSDs. Although TRPML1 activation has shown rescue effects on LSD phenotypes, its activity is pH dependent, and it is blocked by sphingomyelin accumulation, which is characteristic of some LSDs. In contrast, TPC2 activation is pH-independent and not blocked by sphingomyelin, potentially representing an advantage over TRPML1. Here, we discuss the rescue of cellular phenotypes associated with LSDs such as cholesterol and lactosylceramide (LacCer) accumulation or ultrastructural changes seen by electron microscopy, mediated by the small molecule agonist of TPC2, TPC2-A1-P, which promotes lysosomal exocytosis and autophagy. In summary, new data suggest that TPC2 is a promising target for the treatment of different types of LSDs such as MLIV, NPC1, and Batten disease, both in vitro and in vivo.https://www.mdpi.com/2073-4409/11/18/2807TRPMLTRPML3TRPA1TRPM2TRPV2BK |
| spellingShingle | Sandra Prat Castro Veronika Kudrina Dawid Jaślan Julia Böck Anna Scotto Rosato Christian Grimm Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue! Cells TRPML TRPML3 TRPA1 TRPM2 TRPV2 BK |
| title | Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue! |
| title_full | Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue! |
| title_fullStr | Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue! |
| title_full_unstemmed | Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue! |
| title_short | Neurodegenerative Lysosomal Storage Disorders: TPC2 Comes to the Rescue! |
| title_sort | neurodegenerative lysosomal storage disorders tpc2 comes to the rescue |
| topic | TRPML TRPML3 TRPA1 TRPM2 TRPV2 BK |
| url | https://www.mdpi.com/2073-4409/11/18/2807 |
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