Modeling sacsin depletion in Danio Rerio offers new insight on retinal defects in ARSACS

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 106793 - 106793

Published: Jan. 1, 2025

Biallelic mutations in the SACS gene, encoding sacsin, cause early-onset autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disease also characterized by unique and poorly understood retinal abnormalities. While two murine models replicate phenotypic neuronal features observed patients, no phenotype has been described so far. In zebrafish knock-out strain that faithfully mirrors main aspects ARSACS, we impaired visual function due to photoreceptor degeneration, likely caused cell cycle defects progenitor cells. RNA-seq analysis embryos revealed dysfunction proteins related fat-soluble vitamins (e.g., TTPA, RDH5, VKORC) suggested key role neuroinflammation driving defects. Our findings indicate studying pathology ARSACS could be crucial for understanding impact sacsin depletion may offer insights into halting progression.

Language: Английский

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CLN5 deficiency impairs glucose uptake in Batten disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Abstract CLN5 disease, a form of juvenile dementia within the neuronal ceroid lipofuscinosis (NCL), is associated with mutations in gene encoding lysosomal bis(monoacylglycero)phosphate (BMP) synthase, essential for BMP production and function. Limited knowledge cellular mechanisms unclear drug targets hinder translating this to children’s treatment, which remains symptomatic. We developed characterized new cln5 knock-out zebrafish model that replicates key features molecular signatures human disease. Loss Cln5 function vivo altered axonal growth retinal ON-bipolar cells revealing disease features. Additionally, multi-omic analyzes at different developmental stages, revealed an impaired glucose metabolism as original finding NCL. This work demonstrates profound metabolic impact dysfunction, offering promising avenue toward targeted therapies dementia.

Language: Английский

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Trehalose Ameliorates Zebrafish Emotional and Social Deficits Caused by CLN8 Dysfunction

Cells, Journal Year: 2025, Volume and Issue: 14(1), P. 55 - 55

Published: Jan. 5, 2025

CLN8 and other neuronal ceroid lipofuscinoses (NCLs) often lead to cognitive decline, emotional disturbances, social deficits, worsening with disease progression. Disrupted lysosomal pH, impaired autophagy, defective dendritic arborization contribute these symptoms. Using a cln8−/− zebrafish model, we identified significant impairments in locomotion, anxiety, aggression, along subtle deficits interactions, positioning as useful model for therapeutic studies NCL. Our findings show that trehalose, an autophagy enhancer, ameliorates modestly improves behavior predator avoidance mutant zebrafish. This finding aligns animal models clinical reports suggestive of behavioral improvements NCL patients. Trehalose holds promise agent CLN8, warranting further research into its neuroprotective mechanisms applications.

Language: Английский

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CLN5 deficiency impairs glucose uptake and uncovers PHGDH as a potential biomarker in Batten disease

Molecular Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: May 9, 2025

CLN5 disease, a form of juvenile dementia within the neuronal ceroid lipofuscinosis (NCL), is associated with mutations in gene encoding lysosomal bis(monoacylglycero)phosphate (BMP) synthase, essential for BMP production and function. Limited knowledge cellular mechanisms unclear drug targets hinder translating this to children's treatment, which remains symptomatic. We developed characterized new cln5 knock-out zebrafish model that replicates key features molecular signatures human disease. Loss Cln5 function vivo altered axonal growth retinal ON-bipolar cells disrupted calcium homeostasis cerebellum, revealing disease features. Additionally, multi-omic analyses at different developmental stages revealed an impaired glucose metabolism as original finding NCL. A novel biomarker, PHGDH, was validated skin fibroblasts harboring pathogenic variants CLN5, CLN7. also tested metformin improved expression PHGDH patient-derived cells, rescued behavior. This work demonstrates profound metabolic impact dysfunction, offering promising avenue toward targeted therapies dementia.

Language: Английский

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