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

Francis, Vincent; Alshafie, Walaa; Kumar, Rahul; Girard, Martine; Brais, Bernard; McPherson, Peter S.

doi:10.1016/j.jbc.2022.102320

Cited by 19 publications

(23 citation statements)

References 37 publications

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“…Likewise, ALR dysfunction is causally implicated in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a fatal, neurodegenerative disorder, wherein cerebellar Purkinje cells selectively degenerate, leading to spasticity and ataxia ( Bagaria et al, 2022 ; Francis et al, 2022 ). ARSACS is caused by mutations in the gene of sacsin molecular chaperone (SACS), leading to a loss of function phenotype.…”

Section: Autophagic Lysosome Reformation (Alr)mentioning

confidence: 99%

“…ARSACS is caused by mutations in the gene of sacsin molecular chaperone (SACS), leading to a loss of function phenotype. Normally, SACS binds to the motor-protein KIF5B, which is then involved in the extrusion of autolysosome membrane buds along microtubules to create reformation tubules during ALR ( Du et al, 2016 ; Francis et al, 2022 ). Loss of SACS function inhibits the generation of reformation tubules at autolysosomes during ALR, ( Francis et al, 2022 ).…”

Section: Autophagic Lysosome Reformation (Alr)mentioning

confidence: 99%

“…Normally, SACS binds to the motor-protein KIF5B, which is then involved in the extrusion of autolysosome membrane buds along microtubules to create reformation tubules during ALR ( Du et al, 2016 ; Francis et al, 2022 ). Loss of SACS function inhibits the generation of reformation tubules at autolysosomes during ALR, ( Francis et al, 2022 ). In conclusion, ALR plays an important role in maintaining cellular health, and the impairment of this process may contribute to the development of NDs.…”

Section: Autophagic Lysosome Reformation (Alr)mentioning

confidence: 99%

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Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology

Diab

Pilotto

Saxena

2023

Front. Cell. Neurosci.

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The proper functioning of the cell clearance machinery is critical for neuronal health within the central nervous system (CNS). In normal physiological conditions, the cell clearance machinery is actively involved in the elimination of misfolded and toxic proteins throughout the lifetime of an organism. The highly conserved and regulated pathway of autophagy is one of the important processes involved in preventing and neutralizing pathogenic buildup of toxic proteins that could eventually lead to the development of neurodegenerative diseases (NDs) such as Alzheimer’s disease or Amyotrophic lateral sclerosis (ALS). The most common genetic cause of ALS and frontotemporal dementia (FTD) is a hexanucleotide expansion consisting of GGGGCC (G4C2) repeats in the chromosome 9 open reading frame 72 gene (C9ORF72). These abnormally expanded repeats have been implicated in leading to three main modes of disease pathology: loss of function of the C9ORF72 protein, the generation of RNA foci, and the production of dipeptide repeat proteins (DPRs). In this review, we discuss the normal physiological role of C9ORF72 in the autophagy-lysosome pathway (ALP), and present recent research deciphering how dysfunction of the ALP synergizes with C9ORF72 haploinsufficiency, which together with the gain of toxic mechanisms involving hexanucleotide repeat expansions and DPRs, drive the disease process. This review delves further into the interactions of C9ORF72 with RAB proteins involved in endosomal/lysosomal trafficking, and their role in regulating various steps in autophagy and lysosomal pathways. Lastly, the review aims to provide a framework for further investigations of neuronal autophagy in C9ORF72-linked ALS-FTD as well as other neurodegenerative diseases.

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Section: Autophagic Lysosome Reformation (Alr)mentioning

confidence: 99%

Section: Autophagic Lysosome Reformation (Alr)mentioning

confidence: 99%

Section: Autophagic Lysosome Reformation (Alr)mentioning

confidence: 99%

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Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology

Diab

Pilotto

Saxena

2023

Front. Cell. Neurosci.

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“…The domain structure of sacsin provides a link to both the ubiquitin proteasome system and molecular chaperones, suggesting a potential function in protein quality control systems. Although there is some evidence supporting this (Parfitt et al, 2009;Gentil et al, 2019), the precise role of sasin is unknown and it is unclear why its loss results in a complex cellular phenotype that includes mitochondrial dysfunction (Girard et al, 2012a;Bradshaw et al, 2016;Morani et al, 2022), altered intermediate filament cytoskeleton organisation (Lariviere et al, 2015;Duncan et al, 2017;Gentil et al, 2019), altered microtubule dynamics (Francis et al, 2022) and disrupted intracellular trafficking (Romano et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

AlphaFold predicted structure of the Hsp90-like domains of the neurodegeneration linked protein sacsin reveals key residues for ATPase activity

Perna

Castelli

Frasnetti

et al. 2023

Front. Mol. Biosci.

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The ataxia-linked protein sacsin has three regions of partial homology to Hsp90’s N-terminal ATP binding domain. Although a crystal structure for this Hsp90-like domain has been reported the precise molecular interactions required for ATP-binding and hydrolysis are unclear and it is debatable whether ATP biding is compatible with these domains. Furthermore, the Identification of a sacsin domain(s) equivalent to the middle domain of Hsp90 has been elusive. Here we present the superimposition of an AlphaFold structure of sacsin with yeast Hsp90, which provides novel insights into sacsin’s structure. We identify residues within the sacsin Hsp90-like domains that are required for ATP binding and hydrolysis, including the putative catalytic arginine residues equivalent to that of the Hsp90 middle domain. Importantly, our analysis allows comparison of the Hsp90 middle domain with corresponding sacsin regions and identifies a shorter lid segment, in the sacsin ATP-binding domains, than the one found in the N-terminal domain of Hsp90. Our results show how a realignment of residues in the lid segment of sacsin that are involved in ATP binding can better match equivalent residues seen in Hsp90, which we then corroborated using molecular dynamic simulations. We speculate, from a structural viewpoint, why some ATP competitive inhibitors of Hsp90 may not bind sacsin, while others would. Together our analysis supports the hypothesis that sacsin’s function is ATP-driven and would be consistent with it having a role as a super molecular chaperone. We propose that the SR1 regions of sacsin be renamed as HSP-NRD (Hsp90 N-Terminal Repeat Domain; residues 84-324) and the fragment immediately after as HSP-MRD (Hsp90 Middle Repeat Domain; residues 325-518).

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“…This domain structure links sacsin to both the ubiquitin proteasome system and molecular chaperones, suggesting a potential function in protein quality control systems. Although there is some evidence supporting this [6,13], the precise role of sasin is unknown and it is unclear why its loss results in a complex cellular phenotype that includes mitochondrial dysfunction [11,14,15], altered intermediate filament cytoskeleton organisation [13,16,17], altered microtubule dynamics [18] and disrupted intracellular trafficking [19].…”

Section: Introductionmentioning

confidence: 99%

AlphaFold predicted structure of the Hsp90-like domains of the neurodegeneration linked protein sacsin reveals key residues for ATPase activity

Perna

Romano

Prodromou

et al. 2022

Preprint

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The ataxia-linked protein sacsin has three regions of partial homology to Hsp90's N-terminal ATP binding domain. Although a crystal structure for the Hsp90-like domain of sacsin has been reported the precise molecular interactions required for ATP-binding and hydrolysis are unclear. To better understand how sacsin may function as an ATPase we utilized an AlphaFold predicted structure of its Hsp90-like domain. Superimposition onto Hsp90, and other modelling approaches, have resulted in novel insights into sacsin's structure. These encompass identification of residues within the sacsin Hsp90-like domains that are required for ATP binding and hydrolysis, including the catalytic arginine residues equivalent to that of the Hsp90 middle domain. Importantly, our analysis allows comparison of the Hsp90 middle domain with corresponding sacsin regions and has identified that sacsin has a shorter lid segment than the N-terminal domain of Hsp90. We also speculate, from a structural viewpoint, why ATP competitive inhibitors of Hsp90 do not appear to affect sacsin. Together our analysis supports the hypothesis that sacsin's function is ATP-driven and would be consistent with it having a role as a molecular chaperone. We propose that the SR1 regions of sacsin be renamed as HSP-NRD (Hsp90 N-Terminal Repeat Domain; residues 84-324) and the fragment immediately after as HSP-MRD (Hsp90 Middle Repeat Domain; residues 325-518).

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

Cited by 19 publications

References 37 publications

Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology

Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology

AlphaFold predicted structure of the Hsp90-like domains of the neurodegeneration linked protein sacsin reveals key residues for ATPase activity

AlphaFold predicted structure of the Hsp90-like domains of the neurodegeneration linked protein sacsin reveals key residues for ATPase activity

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