GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau DOI Creative Commons

Diana Acosta Ingram,

Emir Turkes, Tae Yeon Kim

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 9, 2025

Lipid dyshomeostasis and tau pathology are present in frontotemporal lobar degeneration (FTLD) Alzheimer's disease (AD). However, the relationship between lipid remains unclear. We report that GRAM Domain Containing 1B (GRAMD1B), a nonvesicular cholesterol transporter, is increased excitatory neurons of human neural organoids (HNOs) with MAPT R406W mutation. Human FTLD, AD cases, PS19 mice also have GRAMD1B expression. show overexpression increases levels free cholesterol, droplets, impairs autophagy flux. Modulating iPSC-derived alters key autophagy-related components such as PI3K, phospho-AKT, p62, well phosphorylated tau, CDK5R1. Blocking function decreases droplets. Knocking down additionally reduces CDK5R1 Our findings elucidate role nervous system highlight its relevance to FTLD AD.

Language: Английский

GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau DOI Creative Commons

Diana Acosta Ingram,

Emir Turkes, Tae Yeon Kim

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 9, 2025

Lipid dyshomeostasis and tau pathology are present in frontotemporal lobar degeneration (FTLD) Alzheimer's disease (AD). However, the relationship between lipid remains unclear. We report that GRAM Domain Containing 1B (GRAMD1B), a nonvesicular cholesterol transporter, is increased excitatory neurons of human neural organoids (HNOs) with MAPT R406W mutation. Human FTLD, AD cases, PS19 mice also have GRAMD1B expression. show overexpression increases levels free cholesterol, droplets, impairs autophagy flux. Modulating iPSC-derived alters key autophagy-related components such as PI3K, phospho-AKT, p62, well phosphorylated tau, CDK5R1. Blocking function decreases droplets. Knocking down additionally reduces CDK5R1 Our findings elucidate role nervous system highlight its relevance to FTLD AD.

Language: Английский

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