Dataset Information

Sacsin, the ARSACS disease protein, controls lysosomal positioning and reformation by regulating microtubule dynamics

ABSTRACT: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a fatal brain disorder featuring cerebellar neurodegeneration leading to spasticity and ataxia. ARSACS is caused by mutations in the SACS gene that encodes sacsin, a massive 4579 amino acid protein with multiple modular domains. Here we demonstrate that sacsin binds to microtubules and regulates microtubule dynamics. Loss of sacsin function in knockout cell lines, knockdown and knockout neurons, and patient fibroblasts leads to alterations in lysosomal transport, positioning, function and reformation following autophagy.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fibroblast

SUBMITTER: Vincent Francis

LAB HEAD: Peter McPherson

PROVIDER: PXD033823 | Pride | 2022-10-15

REPOSITORIES: Pride

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The ARSACS disease protein sacsin controls lysosomal positioning and reformation by regulating microtubule dynamics.

Francis Vincent V Alshafie Walaa W Kumar Rahul R Girard Martine M Brais Bernard B McPherson Peter S PS

The Journal of biological chemistry 20220804 9

Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a fatal brain disorder featuring cerebellar neurodegeneration leading to spasticity and ataxia. This disease is caused by mutations in the SACS gene that encodes sacsin, a massive 4579-amino acid protein with multiple modular domains. However, molecular details of the function of sacsin are not clear. Here, using live cell imaging and biochemistry, we demonstrate that sacsin binds to microtubules and regulates microtubule dynamics. Los ...[more]

PMID: 35933016

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Project description:Reactive oxygen species (ROS) are active molecules involved in several biological functions. When the production of ROS is not counterbalanced by the action of protective antioxidant mechanisms present in living organisms, a condition of oxidative stress can arise with consequent damage to biological structures. The brain is one of the main ROS-generating organs in the human body, with the consequence that most neurological disorders are associated with the overproduction of ROS. Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease associated with mutations in the sacsin gene (SACS). At a cellular level, ARSACS is characterized by mitochondrial impairments, a reduction of bioenergetic processes, and by both an over-production of and an over sensitivity to ROS. Several antioxidant molecules have been proposed as a potential treatment for ARSACS, such as idebenone and resveratrol. Polydopamine nanoparticles (PDNPs) gained significant attention in recent years owing to their peculiar physic-chemical properties, and especially because of their antioxidant activity. PDNPs have shown a great ROS scavenging capacity that, combined with their completely organic nature that grants them the ability to be degraded and excreted by living organisms, make them a promising candidate in the treatment of oxidative stress-related disorders. In this work we assessed the effect of PDNPs upon human fibroblasts; in particular, we investigated the effects of PDNPs on populations of fibroblasts derived from healthy subjects and of fibroblasts derived from ARSACS patients, in terms of antioxidant properties and protein expression. PDNPs interaction with fibroblasts was analyzed in terms of biocompatibility, internalization and uptake pathway, reduction of ROS levels, prevention of ROS-induced apoptosis/necrosis, and protective action upon ROS-induced mitochondrial dysfunctions. Moreover, a complete proteomic analysis of the cells was performed to assess differences in terms of protein expression upon different treatments. Altogether, our data showed that PDNPs can partially counteract ROS-induced damages in both healthy and ARSACS patients-derived fibroblasts, making them a potential therapeutic candidate to treat or at least ameliorate the condition of oxidative stress associated with ARSACS disease.

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