Pathogenic mutation of <scp>UBQLN</scp>2 impairs its interaction with <scp>UBXD</scp>8 and disrupts endoplasmic reticulum‐associated protein degradation

Xia, Yuxing; Yan, Linda; Huang, Bo; Liu, Mujun; Liu, Xionghao; Huang, Cao

doi:10.1111/jnc.12606

Cited by 56 publications

(55 citation statements)

References 28 publications

(46 reference statements)

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“…We speculate that this susceptibility is because they are vulnerable to disturbances in proteostasis, based on the defective properties of mutant UBQLN2 proteins and by extrapolation from other studies. First, our results, like those of others studies, clearly show the UBQLN2 mutants disrupt proteostasis, leading to accumulation of misfolded proteins (13,(28)(29)(30)(31). Second, accumulating evidence suggests disturbance in proteostasis, particularly induction of the UPR, as central in disease pathogenesis caused by ALS mutations in SOD1 and C9ORF72 (45)(46)(47)(48)(49).…”

Section: Discussionsupporting

confidence: 64%

“…On the other hand, it could signify a loss of function, because UBQLN proteins function in autophagy, which typically involves clearance of large aggregates. Other studies have shown ALS-FTD UBQLN2 mutations reduce binding of UBQLN2 with its normal partners, suggesting a possible loss of function (19,22,28). Evidently, understanding how UBQLN2 mutations cause ALS-FTD is important for understanding the mechanisms underlying the disease and for developing novel pharmacotherapies to halt the disease.…”

Section: Als | Motor Neuron Disease | Ubqln2 | Tdp-43 Pathologymentioning

confidence: 99%

“…Indeed, overexpression of the mutant UBQLN2 (mtUBQLN2) proteins in cells and animals support both possibilities. For example, overexpression of ALS mtUBQLN2 proteins caused interference in proteasomal degradation, including perturbation of endoplasmic reticulum-associated degradation (ERAD) (13,(28)(29)(30)(31). The interference in degradation appears to stem from an inability of the mutants to deliver polyubiquitinated proteins to the proteasome for degradation (30,32).…”

Section: Als | Motor Neuron Disease | Ubqln2 | Tdp-43 Pathologymentioning

confidence: 99%

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Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linked UBQLN2 mutations

Chang

Kovlyagina

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS-FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying UBQLN2 mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS-FTD-linked P497S or P506T UBQLN2 mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease. Neuropathologic analysis of the mice with end-stage disease revealed the accumulation of ubiquitinated inclusions in the brain and spinal cord, astrocytosis, a reduction in the number of hippocampal neurons, and reduced staining of TAR-DNA binding protein 43 in the nucleus, with concomitant formation of ubiquitin + inclusions in the cytoplasm of spinal motor neurons. Moreover, both lines displayed denervation muscle atrophy and age-dependent loss of motor neurons that correlated with a reduction in the number of large-caliber axons. By contrast, two mouse lines expressing WT UBQLN2 were mostly devoid of clinical and pathological signs of disease. These UBQLN2 mouse models provide valuable tools for identifying the mechanisms underlying ALS-FTD pathogenesis and for investigating therapeutic strategies to halt disease.A LS is a progressive neurodegenerative disorder associated with loss of upper and lower motor neurons (1, 2). The disease usually manifests in the fifth decade of life, but can occur as early as the late teens. Its hallmark symptoms are progressive muscle weakness, which usually leads to death between 3 and 5 y after first diagnosis. Some patients with ALS also develop frontotemporal dementia (FTD). Genetic findings have linked mutations in different genes to the range of symptoms seen in ALS (3, 4).A common pathologic feature in nearly all ALS cases (∼97%), including all sporadic and most familial cases, is a reduction in TAR-DNA binding protein 43 (TDP-43) in the nucleus and its accumulation in ubiquitin + inclusions in the cytoplasm of spinal motor neurons (5-8). The few exceptions where this pathology is not seen are in ALS cases linked to mutations in the SOD1 and FUS genes (7-10). This has led to speculation that pathogenesis in the vast majority of ALS cases may be mechanistically linked directly or indirectly to TDP-43 pathology (7, 11). Intriguingly, TDP-43 pathology is also a common hallmark of certain forms of FTD where the pathology is found in the brain (5,7,12).Missense mutations (P497H, P497S, P506T, P509S, or P525S) in ubiquilin 2 (UBQLN2) were identified as the cause of X-linked dominant ALS-FTD (13). The afflicted individuals had abnormal inclusions in neurons of the hippocampus and TDP-43 pathology in spinal motor neurons. Additional UBQLN2 mutations have now been identified, and interestingly, like the original mutations, encode missense mutations in the central domain of UBQLN2 protein (14-16). The function of the central domain of UBQLN2 is beginning to em...

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Section: Discussionsupporting

confidence: 64%

Section: Als | Motor Neuron Disease | Ubqln2 | Tdp-43 Pathologymentioning

confidence: 99%

Section: Als | Motor Neuron Disease | Ubqln2 | Tdp-43 Pathologymentioning

confidence: 99%

See 1 more Smart Citation

Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linked UBQLN2 mutations

Chang

Kovlyagina

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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“…A possible explanation for this increase is that excessive amounts of ubiquilin-2 in cells might lead to uncoordinated binding of the protein to ubiquitinated proteins and/or the proteasome, disrupting proteostasis. Another possibility is that overexpression could lead to unregulated binding of ubiquilin-2 to its other partners, such as erasin, UBXD8, hnRNPA1 or with other ubiquilin proteins, all of which have been shown to bind ubiquilin-2 [9, 18, 20]. Such unregulated binding could interfere with either one or both of these protein functions, leading to toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent to this discovery several additional mutations in UBQLN2 have been reported [6–8]. However, the mechanisms by which any of the UBQLN2 mutations cause ALS is not known, although some initial studies of some of them suggest the encoded proteins might interfere with proteasomal degradation [5, 9, 10]. How the mutations interfere with proteasomal degradation is not clear as all of the UBQLN2 mutations described so far map in the central domain of the encoded ubiquilin-2 protein, but not in its surrounding functional ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains, located at the amino-terminus and carboxyl-terminus, respectively [11–13].…”

Section: Introductionmentioning

confidence: 99%

Defective Proteasome Delivery of Polyubiquitinated Proteins by Ubiquilin-2 Proteins Containing ALS Mutations

Chang

Monteiro

2015

PLoS ONE

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Ubiquilin proteins facilitate delivery of ubiquitinated proteins to the proteasome for degradation. Interest in the proteins has been heightened by the discovery that gene mutations in UBQLN2 cause dominant inheritance of amyotrophic lateral sclerosis (ALS). However, the mechanisms by which the mutations cause ALS are not known. Here we report on the underlying defect of ubiquilin-2 proteins containing ALS-linked mutations in affecting proteasome-mediated degradation. We found that overexpression of ubiquilin-2 proteins containing any one of five different ALS mutations slow degradation of Myc, a prototypic proteasome substrate. Examination of coprecipitating proteins indicated that the mutant proteins are generally capable of binding polyubiquitinated proteins, but defective in binding the proteasome. GST-pulldown studies revealed that many of the mutants bind weaker to the S5a subunit of the proteasome, compared with wild type (WT) ubiquilin-2 protein. The results suggest the mutant proteins are unable to deliver their captured cargo to the proteasome for degradation, which presumably leads to toxicity. Quantification of cell death is consistent with this idea. Measurement of protein turnover further indicated the mutant proteins have longer half-lives than WT ubiquilin-2. Our studies provide novel insight into the mechanism by which ALS-linked mutations in UBQLN2 interfere with protein degradation.

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Modeling of Protein Complexes

Scietti

Forneris

2023

Methods in Molecular Biology

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Pathogenic mutation of UBQLN2 impairs its interaction with UBXD8 and disrupts endoplasmic reticulum‐associated protein degradation

Cited by 56 publications

References 28 publications

Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linked UBQLN2 mutations

Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linked UBQLN2 mutations

Defective Proteasome Delivery of Polyubiquitinated Proteins by Ubiquilin-2 Proteins Containing ALS Mutations

Modeling of Protein Complexes

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