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1.
Proc Natl Acad Sci U S A ; 118(40)2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34580197

RESUMO

Ca2+ is the most ubiquitous second messenger in neurons whose spatial and temporal elevations are tightly controlled to initiate and orchestrate diverse intracellular signaling cascades. Numerous neuropathologies result from mutations or alterations in Ca2+ handling proteins; thus, elucidating molecular pathways that shape Ca2+ signaling is imperative. Here, we report that loss-of-function, knockout, or neurodegenerative disease-causing mutations in the lysosomal cholesterol transporter, Niemann-Pick Type C1 (NPC1), initiate a damaging signaling cascade that alters the expression and nanoscale distribution of IP3R type 1 (IP3R1) in endoplasmic reticulum membranes. These alterations detrimentally increase Gq-protein coupled receptor-stimulated Ca2+ release and spontaneous IP3R1 Ca2+ activity, leading to mitochondrial Ca2+ cytotoxicity. Mechanistically, we find that SREBP-dependent increases in Presenilin 1 (PS1) underlie functional and expressional changes in IP3R1. Accordingly, expression of PS1 mutants recapitulate, while PS1 knockout abrogates Ca2+ phenotypes. These data present a signaling axis that links the NPC1 lysosomal cholesterol transporter to the damaging redistribution and activity of IP3R1 that precipitates cell death in NPC1 disease and suggests that NPC1 is a nanostructural disease.


Assuntos
Cálcio/metabolismo , Morte Celular/fisiologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Mitocôndrias/metabolismo , Doença de Niemann-Pick Tipo C/metabolismo , Animais , Transporte Biológico/fisiologia , Linhagem Celular , Colesterol/metabolismo , Retículo Endoplasmático/metabolismo , Feminino , Humanos , Lisossomos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Presenilina-1/metabolismo
2.
EMBO J ; 40(13): e105990, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34019311

RESUMO

Cholesterol and phosphoinositides (PI) are two critically important lipids that are found in cellular membranes and dysregulated in many disorders. Therefore, uncovering molecular pathways connecting these essential lipids may offer new therapeutic insights. We report that loss of function of lysosomal Niemann-Pick Type C1 (NPC1) cholesterol transporter, which leads to neurodegenerative NPC disease, initiates a signaling cascade that alters the cholesterol/phosphatidylinositol 4-phosphate (PtdIns4P) countertransport cycle between Golgi-endoplasmic reticulum (ER), as well as lysosome-ER membrane contact sites (MCS). Central to these disruptions is increased recruitment of phosphatidylinositol 4-kinases-PI4KIIα and PI4KIIIß-which boosts PtdIns4P metabolism at Golgi and lysosomal membranes. Aberrantly increased PtdIns4P levels elevate constitutive anterograde secretion from the Golgi complex, and mTORC1 recruitment to lysosomes. NPC1 disease mutations phenocopy the transporter loss of function and can be rescued by inhibition or knockdown of either key phosphoinositide enzymes or their recruiting partners. In summary, we show that the lysosomal NPC1 cholesterol transporter tunes the molecular content of Golgi and lysosome MCS to regulate intracellular trafficking and growth signaling in health and disease.


Assuntos
Membrana Celular/metabolismo , Complexo de Golgi/metabolismo , Lisossomos/metabolismo , Proteína C1 de Niemann-Pick/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Animais , Transporte Biológico/fisiologia , Células CHO , Linhagem Celular , Colesterol/metabolismo , Cricetulus , Retículo Endoplasmático/metabolismo , Células HEK293 , Humanos , Membranas Intracelulares/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Transdução de Sinais/fisiologia
3.
J Cell Biol ; 218(12): 4141-4156, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31601621

RESUMO

Niemann-Pick type C1 (NPC1) protein is essential for the transport of externally derived cholesterol from lysosomes to other organelles. Deficiency of NPC1 underlies the progressive NPC1 neurodegenerative disorder. Currently, there are no curative therapies for this fatal disease. Given the Ca2+ hypothesis of neurodegeneration, which posits that altered Ca2+ dynamics contribute to neuropathology, we tested if disease mutations in NPC1 alter Ca2+ signaling and neuronal plasticity. We determine that NPC1 inhibition or disease mutations potentiate store-operated Ca2+ entry (SOCE) due to a presenilin 1 (PSEN1)-dependent reduction in ER Ca2+ levels alongside elevated expression of the molecular SOCE components ORAI1 and STIM1. Associated with this dysfunctional Ca2+ signaling is destabilization of neuronal dendritic spines. Knockdown of PSEN1 or inhibition of the SREBP pathway restores Ca2+ homeostasis, corrects differential protein expression, reduces cholesterol accumulation, and rescues spine density. These findings highlight lysosomes as a crucial signaling platform responsible for tuning ER Ca2+ signaling, SOCE, and synaptic architecture in health and disease.


Assuntos
Sinalização do Cálcio , Retículo Endoplasmático/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Plasticidade Neuronal , Animais , Proteínas de Transporte/metabolismo , Colesterol/metabolismo , Espinhas Dendríticas/metabolismo , Fibroblastos/metabolismo , Hipocampo/citologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lisossomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Proteínas de Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Proteína C1 de Niemann-Pick , Proteína ORAI1/metabolismo , Presenilina-1/metabolismo , Transdução de Sinais , Molécula 1 de Interação Estromal/metabolismo , Sinapses/metabolismo
4.
Cell Rep ; 27(9): 2636-2648.e4, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141688

RESUMO

There is increasing evidence that the lysosome is involved in the pathogenesis of a variety of neurodegenerative disorders. Thus, mechanisms that link lysosome dysfunction to the disruption of neuronal homeostasis offer opportunities to understand the molecular underpinnings of neurodegeneration and potentially identify specific therapeutic targets. Here, using a monogenic neurodegenerative disorder, NPC1 disease, we demonstrate that reduced cholesterol efflux from lysosomes aberrantly modifies neuronal firing patterns. The molecular mechanism linking alterations in lysosomal cholesterol egress to intrinsic tuning of neuronal excitability is a transcriptionally mediated upregulation of the ABCA1 transporter, whose PtdIns(4,5)P2-floppase activity decreases plasma membrane PtdIns(4,5)P2. The consequence of reduced PtdIns(4,5)P2 is a parallel decrease in a key regulator of neuronal excitability, the voltage-gated KCNQ2/3 potassium channel, which leads to hyperexcitability in NPC1 disease neurons. Thus, cholesterol efflux from lysosomes regulates PtdIns(4,5)P2 to shape the electrical and functional identity of the plasma membrane of neurons in health and disease.


Assuntos
Membrana Celular/metabolismo , Colesterol/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Lisossomos/metabolismo , Neurônios/fisiologia , Doença de Niemann-Pick Tipo C/fisiopatologia , Fosfatidilinositol 4,5-Difosfato/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Transporte Biológico , Feminino , Canal de Potássio KCNQ2/genética , Canal de Potássio KCNQ2/metabolismo , Canal de Potássio KCNQ3/genética , Canal de Potássio KCNQ3/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo C/metabolismo
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