Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis

Teyssou, Elisa; Chartier, Laura; Amador, Maria-Del-Mar; Lam, Roselina; Lautrette, Géraldine; Nicol, M.; Machat, Selma; Barroca, Sandra Da; Moigneu, Carine; Mairey, Mathilde; Larmonier, Thierry; Saker, Safaa; Dussert, Christelle; Forlani, Sylvie; Fontaine, Bertrand; Seilhean, Danielle; Bohl, Delphine; Boillée, Séverine; Meininger, Vincent; Couratier, Philippe; Salachas, François; Stevanin, Giovanni; Millecamps, Stéphanie

doi:10.1016/j.neurobiolaging.2017.06.018

Cited by 52 publications

(39 citation statements)

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“…6 These mutations segregated with the disease in a dominant (V168M) or recessive (D300V) manner underlying the complexity of ERLIN2 mutation inheritance along the MND spectrum. Such an SP to ALS switch has recently been described for the dominant X-linked UBQLN2 ALS-related gene, 5 and our present results added ERLIN2 as a candidate gene for this form of MND. The mean disease duration before conversion of the phenotype ranged from 20 to 45 years and seemed to be increased when SP disease onset occured earlier.…”

Section: Discussionsupporting

confidence: 84%

“…This patient cohort (including 200 familial and 60 sporadic cases) were screened for C9orf72. 5 Then whole exome sequencing was performed using classical procedures. Exons were captured on the genomic DNA using the SureSelect Clinical Research Exome 50Mb kit (Agilent), followed by massive parallel sequencing on a Hiseq 2000 sequencer (Illumina) at Integragen (Evry, France).…”

Section: Genetic Screeningmentioning

confidence: 99%

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Spastic paraplegia due to recessive or dominant mutations in ERLIN2 can convert to ALS

et al. 2019

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ObjectiveThe aim of this study was to evaluate whether mutations in ERLIN2, known to cause SPG18, a recessive hereditary spastic paraplegia (SP) responsible for the degeneration of the upper motor neurons leading to weakness and spasticity restricted to the lower limbs, could contribute to amyotrophic lateral sclerosis (ALS), a distinct and more severe motor neuron disease (MND), in which the lower motor neurons also profusely degenerates, leading to tetraplegia, bulbar palsy, respiratory insufficiency, and ultimately the death of the patients.MethodsWhole-exome sequencing was performed in a large cohort of 200 familial ALS and 60 sporadic ALS after a systematic screening for C9orf72 hexanucleotide repeat expansion. ERLIN2 variants identified by exome analysis were validated using Sanger analysis. Segregation of the identified variant with the disease was checked for all family members with available DNA.ResultsHere, we report the identification of ERLIN2 mutations in patients with a primarily SP evolving to rapid progressive ALS, leading to the death of the patients. These mutations segregated with the disease in a dominant (V168M) or recessive (D300V) manner in these families or were found in apparently sporadic cases (N125S).ConclusionsInheritance of ERLIN2 mutations appears to be, within the MND spectrum, more complex that previously reported. These results expand the clinical phenotype of ERLIN2 mutations to a severe outcome of MND and should be considered before delivering a genetic counseling to ERLIN2-linked families.

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Section: Discussionsupporting

confidence: 84%

Section: Genetic Screeningmentioning

confidence: 99%

Spastic paraplegia due to recessive or dominant mutations in ERLIN2 can convert to ALS

et al. 2019

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“…This discovery has been corroborated through the use of mutant transgenic mouse models that mimic in vivo symptoms of motor neuron disease and exhibit protein aggregates in the brain Hjerpe et al, 2016). Although the initially identified mutations were all located in the PXX domain of UBQLN2 , recent studies have also identified patients with mutations adjacent to (Teyssou et al, 2017;Williams et al, 2012) and completely outside of (Daoud et al, 2012;Synofzik et al, 2012) this region. The molecular mechanism of neurodegenerative disease due to UBQLN2 mutation remains unknown but could involve progressive accumulation of as-yet-unidentified Ubqln target proteins.…”

Section: Introductionmentioning

confidence: 96%

Global proteomics ofUbqln2-based murine models of ALS

Whiteley

Prado

Poot

et al. 2020

Preprint

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Familial forms of neurodegenerative diseases commonly involve mutation of aggregationprone proteins or components of the protein degradation machinery that act on aberrant proteins. Ubqln2 encodes a member of the UBL/UBA family of proteasome shuttle factors that is thought to facilitate proteasomal degradation of substrates, and mutation of this gene results in a familial form of ALS/FTD in humans. How Ubqln2 dysfunction leads to neurodegeneration, however, remains uncertain. We undertook a comprehensive study to identify proteomic changes upon Ubqln2 perturbation in multiple murine models of Ubqln2-mediated neurodegenerative disease. By performing quantitative multiplexed proteomics on neural tissues of affected animals, we identified a small group of proteins whose abundance is tightly linked to UBQLN2 function: the ubiquitin ligase TRIM32 and two retroelement-derived proteins, PEG10 and CXX1B. Further studies using cultured cells of human origin, including induced neurons, found similar changes in protein abundance upon Ubqln2 loss, and pulse-chase studies suggested that PEG10 and TRIM32 are direct clients of UBQLN2. In conclusion, our study provides a deep understanding of the proteomic landscape of ALS-related Ubqln2 mutants and identifies candidate client proteins that are altered in vivo in disease models and whose degradation is promoted by UBQLN2.

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“…Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons, progressive muscle wasting, and reduced mobility [ 25 , 55 ]. Genetic studies have linked mutations in ubiquilin2 (UBQLN2) to both ALS and frontotemporal lobar degeneration (FTLD) [ 8 , 10 , 48 ]. How UBQLN2 mutations cause neuronal death remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

Mutant UBQLN2P497H in motor neurons leads to ALS-like phenotypes and defective autophagy in rats

Chen

Huang

Shi

et al. 2018

acta neuropathol commun

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Mutations in ubiquilin2 (UBQLN2) have been linked to abnormal protein aggregation in amyotrophic lateral sclerosis (ALS). The mechanisms underlying UBQLN2-related neurodegenerative diseases remain unclear. Using a tetracycline-regulated gene expression system, the ALS-linked UBQLN2P497H mutant was selectively expressed in either the spinal motor neurons or astrocytes in rats. We found that selectively expressing mutant UBQLN2P497H in the spinal motor neurons caused several core features of ALS, including the progressive degeneration of motor neurons, the denervation atrophy of skeletal muscles, and the abnormal protein accumulation. Furthermore, mutant UBQLN2P497H accumulation was associated with an age-dependent decrease in several core autophagy-related proteins. ALS-like phenotypes were not observed when mutant UBQLN2P497H was overexpressed in the astrocytes, however, even though the expression of the mutant UBQLN2P497H protein was higher in these rats. Our results suggest that selectively expressing mutant UBQLN2P497H in motor neurons is sufficient to trigger the development of ALS in rats. Our results further indicate that the compromised autophagy-lysosomal pathway plays a critical role in the pathogenesis of UBQLN2-related neurodegenerative diseases.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0627-9) contains supplementary material, which is available to authorized users.

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Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis

Cited by 52 publications

References 34 publications

Spastic paraplegia due to recessive or dominant mutations in ERLIN2 can convert to ALS

Spastic paraplegia due to recessive or dominant mutations in ERLIN2 can convert to ALS

Global proteomics ofUbqln2-based murine models of ALS

Mutant UBQLN2P497H in motor neurons leads to ALS-like phenotypes and defective autophagy in rats

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