Wild-Type Human TDP-43 Expression Causes TDP-43 Phosphorylation, Mitochondrial Aggregation, Motor Deficits, and Early Mortality in Transgenic Mice

Xu, Ya; Gendron, Tania F.; Zhang, Yong Jie; Lin, Wen Lang; D’Alton, Simon; Hong, Sihui; Casey, Monica Castanedes; Tong, Jimei; Knight, Joshua; Yu, Xin; Rademakers, Rosa; Boylan, Khrista; Hutton, Mike; McGowan, Eileen; Dickson, Dennis W.; Lewis, Jada; Petrucelli, Leonard

doi:10.1523/jneurosci.1630-10.2010

Cited by 474 publications

(503 citation statements)

References 29 publications

(48 reference statements)

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“…The capacity of WT hUBQLN2 to induce toxicity when highly overexpressed is consistent with an increase in cell death seen upon overexpression of the protein in cell cultures, although like our animal studies, there too, toxicity of the WT protein was less potent than ALS-FTD mutant UBQLN2 proteins (30,41). The toxicity caused by overexpression of WT UBQLN2 is not entirely surprising because overexpression of WT SOD1, TDP43, and FUS, all of which are encoded by genes in which mutations cause ALS, generate disease phenotypes (42)(43)(44). Obviously, the mechanism by which overexpression of these different WT proteins cause disease may be unrelated.…”

Section: Discussionsupporting

confidence: 84%

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: 84%

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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“…This concern is indeed echoed by the fact that overexpression of WT TDP-43 itself is sufficient to cause neuronal dysfunction in mice. 16 Hemizygous TDP-43 M337V mice exhibit neuronal death as well as phenotypes with unaltered total TDP-43 expression. Neuronal toxicity in this animal model should be specifically induced by the mutation but not likely as a result of human TDP-43 overexpression.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13][14][15][16][17][18][19][20] However, either premature death before the presence of full behavior impairments or extremely aggressive disease progression in many of these animal models make the interpretation of behavioral and neuropathological measurements, especially cognitive assessment, difficult. The TDP-43 M337V transgenic (Tg) mouse (i.e., Prnp-TARDBP* M337V; The Jackson Laboratory, stock no.…”

Section: Introductionmentioning

confidence: 99%

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization

et al. 2017

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Dominant missense mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the cytoplasmic accumulation of TDP-43 represents a pathological hallmark in ALS and frontotemporal lobar degeneration (FTD). Behavioral investigation of the transgenic mouse model expressing the disease-causing human TDP-43 M337V mutant (TDP-43 M337V mice) is encumbered by premature death in homozygous transgenic mice and a reported lack of phenotype assessed by tail elevation and footprint in hemizygous transgenic mice. Here, using a battery of motor-coordinative and cognitive tests, we report robust motor-coordinative and cognitive deficits in hemizygous TDP-43 M337V mice by 8 months of age. After 12 months of age, cortical neurons are significantly affected by the mild expression of mutant TDP-43, characterized by cytoplasmic TDP-43 mislocalization, mitochondrial dysfunction, and neuronal loss. Compared with age-matched non-transgenic mice, TDP-43 M337V mice demonstrate a similar expression of total TDP-43 but higher levels of TDP-43 in mitochondria. Interestingly, a TDP-43 mitochondrial localization inhibitory peptide abolishes cytoplasmic TDP-43 accumulation, restores mitochondrial function, prevents neuronal loss, and alleviates motor-coordinative and cognitive deficits in adult hemizygous TDP-43 M337V mice. Thus, this study suggests hemizygous TDP-43 M337V mice as a useful animal model to study TDP-43 toxicity and further consolidates mitochondrial TDP-43 as a novel therapeutic target for TDP-43-linked neurodegenerative diseases.

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“…Progranulin is a highly conserved, secreted glycoprotein with multiple functions including regulation of inflammation, stress response, and programmed cell death (Cenik et al, 2012;Petkau and Leavitt, 2014). The holoprotein can be cleaved by proteolytic enzymes into individual granulin peptides, whose function seem to oppose those of progranulin, at least with respect to wound healing (Zhu et al, 2002). Progranulin haploinsufficiency leads to less than half the expected amount of circulating protein (Ghidoni et al, 2008;Finch et al, 2009;Sleegers et al, 2009), possibly due to abundant cleavage of the deficient holoprotein into granulin fragments.…”

Section: Introductionmentioning

confidence: 99%

The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels

Salazar

Butler

Argouarch

et al. 2015

Journal of Neuroscience

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Mutations in the human progranulin gene resulting in protein haploinsufficiency cause frontotemporal lobar degeneration with TDP-43 inclusions. Although progress has been made in understanding the normal functions of progranulin and TDP-43, the molecular interactions between these proteins remain unclear. Progranulin is proteolytically processed into granulins, but the role of granulins in the pathogenesis of neurodegenerative disease is unknown. We used a Caenorhabditis elegans model of neuronal TDP-43 proteinopathy to specifically interrogate the contribution of granulins to the neurodegenerative process. Complete loss of the progranulin gene did not worsen TDP-43 toxicity, whereas progranulin heterozygosity did. Interestingly, expression of individual granulins alone had little effect on behavior. In contrast, when granulins were coexpressed with TDP-43, they exacerbated its toxicity in a variety of behaviors including motor coordination. These same granulins increased TDP-43 levels via a post-translational mechanism. We further found that in human neurodegenerative disease subjects, granulin fragments accumulated specifically in diseased regions of brain. To our knowledge, this is the first demonstration of a toxic role for granulin fragments in a neurodegenerative disease model. These studies suggest that presence of cleaved granulins, rather than or in addition to loss of full-length progranulin, may contribute to disease in TDP-43 proteinopathies.

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Wild-Type Human TDP-43 Expression Causes TDP-43 Phosphorylation, Mitochondrial Aggregation, Motor Deficits, and Early Mortality in Transgenic Mice

Cited by 474 publications

References 29 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

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization

The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels

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