PDZD8 promotes autophagy at ER-Lysosome contact sites to regulate synaptogenesis

Thakur, Rajan S.; O’Connor-Giles, Kate M.

doi:10.1101/2023.10.30.564828

Cited by 5 publications

References 76 publications

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The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1

Wang,

Geng,

Rimal

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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It is well established that DNA Damage Regulated Autophagy Modulator 1 (DRAM1), a lysosomal protein and a target of p53, participates in autophagy. The cellular functions of DRAM1 beyond autophagy remain elusive. Here, we show p53-dependent upregulation of DRAM1 in mitochondrial damage–induced Parkinson’s disease (PD) models and exacerbation of disease phenotypes by DRAM1. We find that the lysosomal location of DRAM1 relies on its intact structure including the cytosol-facing C-terminal domain. Excess DRAM1 disrupts endoplasmic reticulum (ER) structure, triggers ER stress, and induces protective ER-phagy. Mechanistically, DRAM1 interacts with stromal interacting molecule 1 (STIM1) to tether lysosomes to the ER and perturb STIM1 function in maintaining intracellular calcium homeostasis. STIM1 overexpression promotes cellular health by restoring calcium homeostasis, ER stress response, ER-phagy, and AMP-activated protein kinase (AMPK)-Unc-51 like autophagy activating kinase 1 (ULK1) signaling in cells with excess DRAM1. Thus, by promoting organelle contact between lysosomes and the ER, DRAM1 modulates ER structure and function and cell survival under stress. Our results suggest that DRAM1 as a lysosomal protein performs diverse roles in cellular homeostasis and stress response. These findings may have significant implications for our understanding of the role of the p53/DRAM1 axis in human diseases, from cancer to neurodegenerative diseases.

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The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1

Wang,

Geng,

Rimal

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Conserved transcription factors coordinate synaptic gene expression through repression

Kentro,

Singh,

Pham

et al. 2024

Preprint

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Chemical synapses are the primary sites of communication in the nervous system. Synaptogenesis is a complex transcellular process involving hundreds of proteins that must be expressed at the same time. How this spatiotemporal coordination is achieved remains an open question. We find that synaptic genes are broadly and specifically coordinated at the level of transcription across species. Through genomic and functional studies in Drosophila, we demonstrate corresponding coordination of chromatin accessibility and identify chromatin regulators DEAF1 and CLAMP as broad repressors of synaptic gene expression. Disruption of either factor causes increased synaptic gene expression across neuronal subtypes and ectopic synapse formation. We further find that DEAF1, which is implicated in syndromic intellectual disability, is both necessary and sufficient to repress synapse formation. Our findings reveal the critical importance of broad temporally coordinated negative regulation of synaptic gene expression in sculpting neural circuit formation and identify two key repressors.

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Neurodegenerative and neurodevelopmental roles for bulk lipid transportersVPS13AandBLTP2in movement disorders

Neuman,

Thakur,

Gratz

et al. 2024

Preprint

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Background: Bridge-like lipid transfer proteins (BLTPs) mediate bulk lipid transport at membrane contact sites. Mutations in BLTPs are linked to both early-onset neurodevelopmental and later-onset neurodegenerative diseases, including movement disorders. The tissue specificity and temporal requirements of BLTPs in disease pathogenesis remain poorly understood. Objectives: To determine the age-of-onset and tissue-specific roles of VPS13A and BLTP2 in movement disorder pathogenesis using Drosophila models. Methods: We generated tissue-specific knockdowns of the VPS13A ortholog (Vps13) and the BLTP2 ortholog (hobbit) in neurons and muscles of Drosophila. We analyzed age-dependent locomotor behavior, neurodegeneration, and synapse development and function. Results: Neuron-specific loss of the VPS13A ortholog caused neurodegeneration followed by age-onset movement deficits and reduced lifespan, while muscle-specific loss affected only lifespan, revealing neurodegeneration and myopathy as independent comorbidities in VPS13A disease. In contrast, neuronal loss of the BLTP2 ortholog resulted in severe early-onset locomotor defects without neurodegeneration, while muscle loss impaired synaptogenesis and neurotransmission at the neuromuscular junction (NMJ). Conclusions: VPS13A maintains neuronal survival, while BLTP2 orchestrates synaptic development. VPS13A function in muscle does not play a role in movement defects. The phenotypic specificity of BLTP function provides mechanistic insights into distinct disease trajectories for BLTP-associated movement disorders.

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PDZD8 promotes autophagy at ER-Lysosome contact sites to regulate synaptogenesis

Cited by 5 publications

References 76 publications

The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1

The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1

Conserved transcription factors coordinate synaptic gene expression through repression

Neurodegenerative and neurodevelopmental roles for bulk lipid transportersVPS13AandBLTP2in movement disorders

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