UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosis

Williams, Kelly L.; Warraich, Sadaf T.; Yang, Shu; Solski, Jennifer A.; Fernando, Ruvini; Rouleau, Guy A.; Nicholson, Garth A.; Blair, Ian P.

doi:10.1016/j.neurobiolaging.2012.05.008

Cited by 123 publications

(137 citation statements)

References 20 publications

Supporting

Mentioning

128

Contrasting

Unclassified

Order By: Relevance

“…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)(15)(16). The function of the central domain of UBQLN2 is beginning to emerge with studies showing it assists in chaperone function (17)(18)(19) and in docking the protein with different adaptors of its function (20)(21)(22).…”

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

confidence: 99%

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.

110

View full text Add to dashboard Cite

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...

show abstract

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

confidence: 99%

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.

110

View full text Add to dashboard Cite

show abstract

“…Ubiquilin-2 immunoreactivity has been shown to co-localize with that of ubiquitin [29]. A case with a (c.1460C[T, p.Thr4871le) UBQLN2 mutation did show anterior horn motor neurons positive for ubiquilin-2 as well as TDP-43, ubiquitin, and FUS [127].…”

Section: Ubqln2mentioning

confidence: 99%

The genetics and neuropathology of amyotrophic lateral sclerosis

et al. 2012

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons leading to death from respiratory failure within about 3 years of symptom onset. A family history of ALS is obtained in about 5 % but the distinction between familial and apparently sporadic ALS is artificial and genetic factors play a role in all types. For several years, only one gene was known to have a role in ALS pathogenesis, SOD1. In the last few years there has been a rapid advance in our genetic knowledge of the causes of ALS, and the relationship of the genetic subtypes with pathological subtypes and clinical phenotype. Mutations in the gene for TDP-43 protein, TARDBP, highlight this, with pathology mimicking closely that found in other types of ALS, and a phenotypic spectrum that includes frontotemporal dementia. Mutations in the FUS gene, closely related to TDP-43, lead to a similar clinical phenotype but distinct pathology, so that the three pathological groups represented by SOD1, TARDBP, and FUS are distinct. In this review, we explore the genetic architecture of ALS, highlight some of the genes implicated in pathogenesis, and describe their phenotypic range and overlap with other diseases.

show abstract

“…UBQLN2 alterations have been reported in sporadic ALS and familial ALS cases [61]. Further, UBQLN2 and ubiquitin co-localize in pathological inclusions and they also contain TDP43, FUS/ TLS or OPTN [61,63], suggesting that altered proteostasis is involved as a pathogenic mechanism in ALS. On the other hand, p62/SQSTM1 is a well-described autophagy substrate that acts as an adaptor protein that bridges aggregates and autophagy clearance, through the binding with LC3 [64].…”

Section: Genetic Alterations To the Autophagy Pathway In Alsmentioning

confidence: 97%

“…Alterations in autophagic genes UBQLN2, p62/SQSTM1, OPTN, VCP, CHMP2B, and FIG4 proteins is also linked with ALS, and in some cases frontotemporal dementia ( FTD). These ubiquilin protein) [61][62][63], SQSTM1 (coding for p62/SQSTM1 protein) [64][65][66], OPTN (coding for optineurin protein, OPTN) [67][68][69][70] and VCP (coding Valosincontaining protein, VCP) [71] that are directly involved in protein degradation, and in CHMP2B (coding for charged multivesicular body protein 2B, or chromatinmodifying 2B, CHMP2B) [72,73] and FIG4 (coding for FIG4 protein) [74] that are required for autophagosome maturation. UBQLN2 is a protein that transports polyubiquinated proteins to the degradation processes by proteasome and autophagy; and ALS-linked mutations in this gene may impair overall protein degradation [61].…”

Section: Genetic Alterations To the Autophagy Pathway In Alsmentioning

confidence: 99%

Dual Role of Autophagy in Neurodegenerative Diseases: The Case of Amyotrophic Lateral Sclerosis

Bargsted

Vidal

Hetz

et al. 2015

Current Topics in Neurotoxicity

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is an adult onset and fatal neurodegenerative disease. A major histophatological hallmark of the disease patient-derived tissue and ALS mouse models is the presence of protein aggregates containing misfolded specific proteins. Strategies to clear out these abnormal protein species are proposed as a possible target for disease intervention. Autophagy, a catabolic route that selective degradates abnormally-folded proteins by the lysosomal pathway, has emerged as an attractive target to treat neurodegenerative diseases, like ALS. Accumulating evidence indicates that autophagy impairment also occurs in ALS and can contribute to the neurodegenerative condition. In this article we discuss the evidence involving autophagy alteration associated to ALS phenotype and the evidence that place autophagy as a therapeutic opportunity to treat this neurodegenerative disease.

show abstract

UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosis

Cited by 123 publications

References 20 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

The genetics and neuropathology of amyotrophic lateral sclerosis

Dual Role of Autophagy in Neurodegenerative Diseases: The Case of Amyotrophic Lateral Sclerosis

Contact Info

Product

Resources

About