ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones
- PMID: 17989065
- DOI: 10.1093/hmg/ddm324
ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones
Abstract
It is estimated that more than 40 different lysosomal storage disorders (LSDs) cumulatively affect one in 5000 live births, and in the majority of the LSDs, neurodegeneration is a prominent feature. Neuronal ceroid lipofuscinoses (NCLs), as a group, represent one of the most common (one in 12,500 births) neurodegenerative LSDs. The infantile NCL (INCL) is the most devastating neurodegenerative LSD, which is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. We previously reported that neuronal death by apoptosis in INCL, and in the PPT1-knockout (PPT1-KO) mice that mimic INCL, is at least in part caused by endoplasmic reticulum (ER) and oxidative stresses. In the present study, we sought to determine whether ER and oxidative stresses are unique manifestations of INCL or they are common to both neurodegenerative and non-neurodegenerative LSDs. Unexpectedly, we found that ER and oxidative stresses are common manifestations in cells from both neurodegenerative and non-neurodegenerative LSDs. Moreover, all LSD cells studied show extraordinary sensitivity to brefeldin-A-induced apoptosis, which suggests pre-existing ER stress conditions. Further, we uncovered that chemical disruption of lysosomal homeostasis in normal cells causes ER stress, suggesting a cross-talk between the lysosomes and the ER. Most importantly, we found that chemical chaperones that alleviate ER and oxidative stresses are also cytoprotective in all forms of LSDs studied. We propose that ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative LSDs and suggest that the beneficial effects of chemical/pharmacological chaperones are exerted, at least in part, by alleviating these stress conditions.
Similar articles
-
Cln1 gene disruption in mice reveals a common pathogenic link between two of the most lethal childhood neurodegenerative lysosomal storage disorders.Hum Mol Genet. 2015 Oct 1;24(19):5416-32. doi: 10.1093/hmg/ddv266. Epub 2015 Jul 9. Hum Mol Genet. 2015. PMID: 26160911 Free PMC article.
-
Palmitoyl-protein thioesterase-1 deficiency leads to the activation of caspase-9 and contributes to rapid neurodegeneration in INCL.Hum Mol Genet. 2006 May 15;15(10):1580-6. doi: 10.1093/hmg/ddl078. Epub 2006 Mar 28. Hum Mol Genet. 2006. PMID: 16571600
-
Cln3-mutations underlying juvenile neuronal ceroid lipofuscinosis cause significantly reduced levels of Palmitoyl-protein thioesterases-1 (Ppt1)-protein and Ppt1-enzyme activity in the lysosome.J Inherit Metab Dis. 2019 Sep;42(5):944-954. doi: 10.1002/jimd.12106. Epub 2019 May 14. J Inherit Metab Dis. 2019. PMID: 31025705 Free PMC article.
-
Mitochondrial Dysfunction and Neurodegeneration in Lysosomal Storage Disorders.Trends Mol Med. 2017 Feb;23(2):116-134. doi: 10.1016/j.molmed.2016.12.003. Epub 2017 Jan 19. Trends Mol Med. 2017. PMID: 28111024 Review.
-
Lysosomal storage diseases--the horizon expands.Nat Rev Neurol. 2013 Oct;9(10):583-98. doi: 10.1038/nrneurol.2013.163. Epub 2013 Aug 13. Nat Rev Neurol. 2013. PMID: 23938739 Review.
Cited by
-
p62/SQSTM1 prominently accumulates in renal proximal tubules in nephropathic cystinosis.Pediatr Nephrol. 2012 Nov;27(11):2137-2144. doi: 10.1007/s00467-012-2227-4. Epub 2012 Jun 20. Pediatr Nephrol. 2012. PMID: 22714671
-
Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease).Biochim Biophys Acta. 2013 Nov;1832(11):1906-9. doi: 10.1016/j.bbadis.2013.05.026. Epub 2013 Jun 6. Biochim Biophys Acta. 2013. PMID: 23747979 Free PMC article. Review.
-
GFAP hyperpalmitoylation exacerbates astrogliosis and neurodegenerative pathology in PPT1-deficient mice.Proc Natl Acad Sci U S A. 2021 Mar 30;118(13):e2022261118. doi: 10.1073/pnas.2022261118. Proc Natl Acad Sci U S A. 2021. PMID: 33753498 Free PMC article.
-
Cln1 gene disruption in mice reveals a common pathogenic link between two of the most lethal childhood neurodegenerative lysosomal storage disorders.Hum Mol Genet. 2015 Oct 1;24(19):5416-32. doi: 10.1093/hmg/ddv266. Epub 2015 Jul 9. Hum Mol Genet. 2015. PMID: 26160911 Free PMC article.
-
Upregulation of the Rab27a-dependent trafficking and secretory mechanisms improves lysosomal transport, alleviates endoplasmic reticulum stress, and reduces lysosome overload in cystinosis.Mol Cell Biol. 2013 Aug;33(15):2950-62. doi: 10.1128/MCB.00417-13. Epub 2013 May 28. Mol Cell Biol. 2013. PMID: 23716592 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
Miscellaneous