The ataxia protein sacsin is required for integrin trafficking and synaptic organization

Romano, Lisa E.L.; Aw, Wen; Hixson, Kathryn; Novoselova, Tatiana V.; Havener, Tammy M.; Howell, Stefanie; Hall, Charlotte; Xing, Lei; Beri, Josh; Nethisinghe, Suran; Perna, Laura; Hatimy, Abubakar; Altadonna, Ginevra Chioccioli; Graves, Lee M.; Herring, Laura E.; Hickey, Anthony; Thalassinos, Konstantinos; Chapple, J. Paul; Wolter, Justin M.

doi:10.1101/2021.08.20.456807

Cited by 2 publications

(8 citation statements)

References 80 publications

(98 reference statements)

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“…With hiPSC cells, it may be difficult to model aging-related diseases [ 16 ]. SH-SY5Y cells with sacsin knockout may also be a promising approach to monitor the alterations of gene/protein expression or cellular changes [ 17 , 18 ]. Since SH-SY5Y are widely used cell lines in neuroscience and are low-cost human-derived cell lines, these can be used to differentiate various neuronal phenotypes [ 18 ].…”

Section: Sacsin Functions and Cell/animal Models Of Arsacsmentioning

confidence: 99%

“…A recent study by Romano et al [ 17 ] revealed that, besides controlling the filament architecture, sacsin could play a crucial role in cell adhesion, microtubule organization and trafficking proteins. The mentioned authors provided an extensive study on the possible functions of sacsin.…”

Section: Sacsin Protein Domainsmentioning

confidence: 99%

“…Additionally, sacsin may interact with exosomes, which could also impact several chaperons or microtubule-related mechanisms. Figure 2 demonstrates that sacsin may serve as a critical regulator of different cellular processes, including chaperon activity, the transport of vesicles and microtubule and filament organization [ 17 ].…”

Section: Sacsin Protein Domainsmentioning

confidence: 99%

“…Currently, SACS has only been related to ARSACS. According to several studies on non-functional sacsin or sacsin knockout in cell lines or mice, sacsin is involved in various cellular roles, such as chaperon functions, mitochondrial mechanisms, microtubule filament control and cell adhesion [ 17 ]. It may not be ruled out that sacsin could exert an impact, directly or indirectly, in other types of neurodegenerative diseases (especially ataxias) than ARSACS.…”

Section: Potential Involvement Of Sacs In Other Neurodegenerative Diseasesmentioning

confidence: 99%

“…In sacsin knockout cells, the modulation of PTEN-FAK signaling could improve the ARSACS-related cellular dysfunctions, including microtubule organization, cell migration or adhesion [ 17 ]. PTEN has been verified as a negative regulator of focal adhesion.…”

Section: Arsacs Diagnosis and Potential Therapeuticsmentioning

confidence: 99%

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Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

Bagaria

Bagyinszky

2022

IJMS

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Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases.

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Section: Sacsin Functions and Cell/animal Models Of Arsacsmentioning

confidence: 99%

Section: Sacsin Protein Domainsmentioning

confidence: 99%

Section: Sacsin Protein Domainsmentioning

confidence: 99%

Section: Potential Involvement Of Sacs In Other Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Arsacs Diagnosis and Potential Therapeuticsmentioning

confidence: 99%

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Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

Bagaria

Bagyinszky

2022

IJMS

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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 ataxia protein sacsin is required for integrin trafficking and synaptic organization

Cited by 2 publications

References 80 publications

Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

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

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