Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration

Seelaar, Harro; Klijnsma, Kirsten Y.; Koning, Inge de; Lugt, Aad van der; Chiu, Wang Zheng; Azmani, Asma; Rozemüller, Annemieke; Swieten, John van

doi:10.1007/s00415-009-5404-z

Cited by 133 publications

(113 citation statements)

References 27 publications

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“…The few exceptions where this pathology is not seen are in ALS cases linked to mutations in the SOD1 and FUS genes (7)(8)(9)(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).…”

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.

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: 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.

111

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“…16,28 Previously, we have shown the Drosophila p62 homologue, Ref(2)P co-localizes with ubiquitin positive neural inclusions in Atg8a and bchs mutants, as well as in very old wild-type flies at a time when autophagic function is suppressed (8 weeks). 17,19 To determine if Ref(2)P shows a shift in solubility pattern that is similar to IUP profiles we examined Ref(2)P levels from neural preparation taken at different ages and from flies were autophagic activity was genetically altered.…”

Section: Ref(2)p Profiles Reflect Age-dependent and Genetic Changes Tmentioning

confidence: 99%

“…55 FTD3 patients have extensive and early onset neurological disorders that include the formation of neural aggregates containing ubiquitin. 28,56 To examine this further we ectopically expressed in HeLa cells a mutant form of CHMP2B (ESCRT-III subunit, CHMP2B-intron5), which corresponds to a genetic defect found in FTD3 patients. 22 Expression of mutant CHMP2B in HeLa cells causes a significant accumulation of p62 and ubiquitin, as analyzed by immunoblots and immunoflourescence microscopy.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 99%

p62, Ref(2)P and ubiquitinated proteins are conserved markers of neuronal aging, aggregate formation and progressive autophagic defects

Bartlett¹,

Isakson²,

Lewerenz³

et al. 2011

Autophagy

194

216

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“…They include atypical cases of FTLD-U, basophilic inclusion body disease, and neuronal intermediate filament inclusion body disease (Munoz et al 2009;Neumann et al 2009a,b). Neuroimaging of FTLD-FUS shows atrophy of frontoinsular and cingulate cortex, and of the head of the caudate nucleus (Josephs et al 2010;Seelaar et al 2010). FTD-FUS should be suspected when disease onset is before 40 years of age, in the absence of a family history of FTD, and the presence of caudate atrophy.…”

Section: Ftld-fusmentioning

confidence: 99%

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

Goedert¹,

Ghetti²,

Spillantini³

2011

Cold Spring Harbor Perspectives in Medicine

138

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Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration

Cited by 133 publications

References 27 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

p62, Ref(2)P and ubiquitinated proteins are conserved markers of neuronal aging, aggregate formation and progressive autophagic defects

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

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