NAADP-Evoked Ca[sup.2+] Signaling Leads to Mutant Huntingtin Aggregation and Autophagy Impairment in Murine Astrocytes
Huntington's disease (HD) is a progressive neurodegenerative disease characterized by mutations in the huntingtin gene (mHtt), causing an unstable repeat of the CAG trinucleotide, leading to abnormal long repeats of polyglutamine (poly-Q) in the N-terminal region of the huntingtin, which form a...
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Published in | International journal of molecular sciences Vol. 24; no. 6 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
MDPI AG
01.03.2023
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Subjects | |
Online Access | Get full text |
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Summary: | Huntington's disease (HD) is a progressive neurodegenerative disease characterized by mutations in the huntingtin gene (mHtt), causing an unstable repeat of the CAG trinucleotide, leading to abnormal long repeats of polyglutamine (poly-Q) in the N-terminal region of the huntingtin, which form abnormal conformations and aggregates. Alterations in Ca[sup.2+] signaling are involved in HD models and the accumulation of mutated huntingtin interferes with Ca[sup.2+] homeostasis. Lysosomes are intracellular Ca[sup.2+] storages that participate in endocytic and lysosomal degradation processes, including autophagy. Nicotinic acid adenine dinucleotide phosphate (NAADP) is an intracellular second messenger that promotes Ca[sup.2+] release from the endo-lysosomal system via Two-Pore Channels (TPCs) activation. Herein, we show the impact of lysosomal Ca[sup.2+] signals on mHtt aggregation and autophagy blockade in murine astrocytes overexpressing mHtt-Q74. We observed that mHtt-Q74 overexpression causes an increase in NAADP-evoked Ca[sup.2+] signals and mHtt aggregation, which was inhibited in the presence of Ned-19, a TPC antagonist, or BAPTA-AM, a Ca[sup.2+] chelator. Additionally, TPC2 silencing revert the mHtt aggregation. Furthermore, mHtt has been shown co-localized with TPC2 which may contribute to its effects on lysosomal homeostasis. Moreover, NAADP-mediated autophagy was also blocked since its function is dependent on lysosomal functionality. Taken together, our data show that increased levels of cytosolic Ca[sup.2+] mediated by NAADP causes mHtt aggregation. Additionally, mHtt co-localizes with the lysosomes, where it possibly affects organelle functions and impairs autophagy. |
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ISSN: | 1422-0067 1422-0067 |
DOI: | 10.3390/ijms24065593 |