Increased mitochondrial calcium uptake and concomitant mitochondrial activity by presenilin loss promotes mTORC1 signaling to drive neurodegeneration

Ryan, Kerry C.; Ashkavand, Zahra; Sarasija, Shaarika; Laboy, Jocelyn T.; Samarakoon, Rohan; Norman, Kenneth R.

doi:10.1111/acel.13472

Cited by 14 publications

(8 citation statements)

References 111 publications

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“…Consistently, we have reported that loss of the C. elegans presenilin 1 orthologue SEL-12 results in a loss of proteostasis [17] and disrupts autophagy [18]. In addition, we found that the proteostasis defects observed in sel-12 mutants were dependent upon an aberrant elevation in mitochondrial calcium levels [17,18]. There is also evidence that presenilin is necessary for proper lysosome function [10,11,[19][20][21][22].…”

Section: Introductionsupporting

confidence: 85%

“…Indeed, fAD presenilin mutations are associated with autophagy defects at multiple stages in the process including initiation, autophagosome maturation, autophagosome fusion with lysosomes, and cargo degradation by the lysosomes [16]. Consistently, we have reported that loss of the C. elegans presenilin 1 orthologue SEL-12 results in a loss of proteostasis [17] and disrupts autophagy [18]. In addition, we found that the proteostasis defects observed in sel-12 mutants were dependent upon an aberrant elevation in mitochondrial calcium levels [17,18].…”

Section: Introductionsupporting

confidence: 74%

“…To help understand the mechanism connecting mitochondrial calcium dyshomeostasis and lysosome function in sel-12 mutants, we explored the impact mitochondrial reactive oxygen species (ROS) have on lysosome function. Previously, we demonstrated that sel-12 mutants show evidence of elevated oxidative stress [13,18]. In sel-12 mutants, increased mitochondrial calcium accumulation disrupts mitochondrial activity and results in increased mitochondrial ROS generation.…”

Section: Lysosome Defects Are Alleviated By Mitochondrialtargeted Ant...mentioning

confidence: 91%

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C. elegans Presenilin Mediates Inter-Organelle Contacts and Communication that Is Required for Lysosome Activity

2024

Aging dis

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Compromised lysosome function is implicated in the pathology of many neurodegenerative diseases, including Alzheimer's disease (AD). Familial Alzheimer's disease (fAD) is caused primarily by mutations in the presenilin encoding genes, but the underlying mechanism remains obscure. Loss of the conserved C. elegans presenilin orthologue SEL-12 results in increased mitochondrial calcium, which promotes neurodegeneration. Here, we find that sel-12 mutant lysosomes, independent of SEL-12 proteolytic activity, are significantly enlarged and more alkaline due to increased ER-to-mitochondrial calcium signaling and concomitant mitochondrial oxidative stress. These defects and their dependence on mitochondrial calcium are recapitulated in human fAD fibroblasts, demonstrating a conserved role for mitochondrial calcium in presenilin-mediated lysosome dysfunction. sel-12 mutants also have increased contact surface area between the ER, mitochondria, and lysosomes, suggesting sel-12 has an additional role in modulating organelle contact and communication. Overall, we demonstrate that SEL-12 maintains lysosome acidity and lysosome health by controlling ER-to-mitochondrial calcium signaling.

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Section: Introductionsupporting

confidence: 85%

Section: Introductionsupporting

confidence: 74%

Section: Lysosome Defects Are Alleviated By Mitochondrialtargeted Ant...mentioning

confidence: 91%

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C. elegans Presenilin Mediates Inter-Organelle Contacts and Communication that Is Required for Lysosome Activity

2024

Aging dis

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“…In addition, mutations in sel-12 result in the hyperactivation of the mTORC1 pathway, due to increased mitochondrial Ca 2+ and consequent mitochondrial activation and increased energy production. This hyperactivation of mTORC1 potentiates defects in proteostasis and neurodegeneration, and blockade of mTORC1 allows for partial reversal of the proteostasis defects and neurodegenerative phenotypes of sel-12 mutants [ 96 ].…”

Section: C Elegans Models To Study the Function Of Presenilinsmentioning

confidence: 99%

Modeling Alzheimer’s Disease in Caenorhabditis elegans

et al. 2022

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Alzheimer’s disease (AD) is the most frequent cause of dementia. After decades of research, we know the importance of the accumulation of protein aggregates such as β-amyloid peptide and phosphorylated tau. We also know that mutations in certain proteins generate early-onset Alzheimer’s disease (EOAD), and many other genes modulate the disease in its sporadic form. However, the precise molecular mechanisms underlying AD pathology are still unclear. Because of ethical limitations, we need to use animal models to investigate these processes. The nematode Caenorhabditis elegans has received considerable attention in the last 25 years, since the first AD models overexpressing Aβ peptide were described. We review here the main results obtained using this model to study AD. We include works studying the basic molecular mechanisms of the disease, as well as those searching for new therapeutic targets. Although this model also has important limitations, the ability of this nematode to generate knock-out or overexpression models of any gene, single or combined, and to carry out toxicity, recovery or survival studies in short timeframes with many individuals and at low cost is difficult to overcome. We can predict that its use as a model for various diseases will certainly continue to increase.

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“…In human hepatocellular carcinoma, elevated Glypican-3 expression is associated with the suppression of autophagy, and reducing GPC3 elevates autophagy levels and suppresses cell growth [66][67][68] . In contrast to the effects of lowering heparan sulfate-modified protein function, mutations in PSEN1 compromise autophagosome to lysosome flux [69][70][71][72] , and activating autophagy can restore autophagy levels and rescue mitochondrial abnormalities 73 . These findings point to the regulation of autophagy as a key element of AD pathogenesis, and heparan sulfatemodified proteins as an important determinant of autophagy flux.…”

Section: Transcriptome Patterns and Cellular Events Affected By Hepar...mentioning

confidence: 99%

Heparan sulfate modified proteins affect cellular processes central to neurodegeneration and modulatepresenilinfunction

Schultheis,

Connell,

Kapral

et al. 2024

Preprint

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Mutations in presenilin-1 (PSEN1) are the most common cause of familial, early-onset Alzheimer's disease (AD), typically producing cognitive deficits in the fourth decade. A variant of APOE, APOE3 Christchurch (APOE3ch), was found associated with protection from both cognitive decline and Tau accumulation in a 70-year-old bearing the disease-causing PSEN1-E280A mutation. The amino acid change in ApoE3ch is within the heparan sulfate (HS) binding domain of APOE, and purified APOEch showed dramatically reduced affinity for heparin, a highly sulfated form of HS. The physiological significance of ApoE3ch is supported by studies of a mouse bearing a knock-in of this human variant and its effects on microglia reactivity and Aβ-induced Tau deposition. The studies reported here examine the function of heparan sulfate-modified proteoglycans (HSPGs) in cellular and molecular pathways affecting AD-related cell pathology in human cell lines and mouse astrocytes. The mechanisms of HSPG influences on presenilin-dependent cell loss and pathology were evaluated in Drosophila using knockdown of the presenilin homolog, Psn, together with partial loss of function of sulfateless (sfl), a homolog of NDST1, a gene specifically affecting HS sulfation. HSPG modulation of autophagy, mitochondrial function, and lipid metabolism were shown to be conserved in cultured human cell lines, Drosophila, and mouse astrocytes. RNAi of Ndst1 reduced intracellular lipid levels in wild-type mouse astrocytes or those expressing humanized variants of APOE, APOE3, and APOE4. RNA-sequence analysis of human cells deficient in HS synthesis demonstrated effects on the transcriptome governing lipid metabolism, autophagy, and mitochondrial biogenesis and showed significant enrichment in AD susceptibility genes identified by GWAS. Neuron-directed knockdown of Psn in Drosophila produced cell loss in the brain and behavioral phenotypes, both suppressed by simultaneous reductions in sfl mRNA levels. Abnormalities in mitochondria, liposome morphology, and autophagosome-derived structures in animals with Psn knockdown were also rescued by simultaneous reduction of sfl. sfl knockdown reversed Psn-dependent transcript changes in genes affecting lipid transport, metabolism, and monocarboxylate carriers. These findings support the direct involvement of HSPGs in AD pathogenesis.

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Increased mitochondrial calcium uptake and concomitant mitochondrial activity by presenilin loss promotes mTORC1 signaling to drive neurodegeneration

Cited by 14 publications

References 111 publications

C. elegans Presenilin Mediates Inter-Organelle Contacts and Communication that Is Required for Lysosome Activity

C. elegans Presenilin Mediates Inter-Organelle Contacts and Communication that Is Required for Lysosome Activity

Modeling Alzheimer’s Disease in Caenorhabditis elegans

Heparan sulfate modified proteins affect cellular processes central to neurodegeneration and modulatepresenilinfunction

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