HO-1 induction in motor cortex and intestinal dysfunction in TDP-43 A315T transgenic mice

Guo, Yansu; Wang, Qian; Zhang, Kunxi; An, Ting; Shi, Pengxiao; Li, Zhongyao; Duan, Weisong; Li, Chunyan

doi:10.1016/j.brainres.2012.04.003

Cited by 65 publications

(58 citation statements)

References 25 publications

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“…Apart from expression levels, the differences in survival between TDP-43 transgenic lines may further be attributed to different promoters used for expression [21,37,46], or genetic backgrounds used [5]. Furthermore, reduced survival of mutant TDP-43 transgenic mice driven by the prion promoter has been linked to bowel paralysis [11,14,16].…”

Section: Discussionmentioning

confidence: 99%

Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Hummel

Stevens³

et al. 2015

Acta Neuropathol

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The nuclear transactive response DNA-binding protein 43 (TDP-43) undergoes relocalization to the cytoplasm with formation of cytoplasmic deposits in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathogenic mutations in the TDP-43-encoding TARDBP gene in familial ALS as well as non-mutant human TDP-43 have been utilized to model FTD/ALS in cell culture and animals, including mice. Here, we report novel A315T mutant TDP-43 transgenic mice, iTDP-43(A315T), with controlled neuronal over-expression. Constitutive expression of human TDP-43(A315T) resulted in pronounced early-onset and progressive neurodegeneration, which was associated with compromised motor performance, spatial memory and disinhibition. Muscle atrophy resulted in reduced grip strength. Cortical degeneration presented with pronounced astrocyte activation. Using differential protein extraction from iTDP-43(A315T) brains, we found cytoplasmic localization, fragmentation, phosphorylation and ubiquitination and insolubility of TDP-43. Surprisingly, suppression of human TDP-43(A315T) expression in mice with overt neurodegeneration for only 1 week was sufficient to significantly improve motor and behavioral deficits, and reduce astrogliosis. Our data suggest that functional deficits in iTDP-43(A315T) mice are at least in part a direct and transient effect of the presence of TDP-43(A315T). Furthermore, it illustrates the compensatory capacity of compromised neurons once transgenic TDP-43 is removed, with implications for future treatments.

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Section: Discussionmentioning

confidence: 99%

Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Hummel

Stevens³

et al. 2015

Acta Neuropathol

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“…A link between the motor system and the ENS has been found in a mouse model, where lack of GDNF (glial cell line-derived neurotrophic factor - a potent protective factor for motor neurones) leads to considerable loss of ENS neurones [89], while the receptor tyrosine kinase Ret (c-Ret), which transduces GDNF signalling, is highly expressed by a specific subtype of enteric neurons in the human ENS [90]. Furthermore, the TDP-43 mouse model of ALS exhibits intestinal dysfunction characterized by a progressively thinned colon, swollen small intestine, reduced food intake, and increased TDP-43 accumulation in the myenteric nerve plexus, which contributes to death independent of muscular weakness [91,92]. In addition to animal models of ALS manifesting abnormalities of the gut, autonomic dysfunction has been described in ALS patients [44], with reports of subclinical gastrointestinal motor dysfunction [43], delayed colonic transit times [93], delayed gastric emptying [94], and an increased prevalence of constipation [95].…”

Section: Meeting Energy Needs In Alsmentioning

confidence: 99%

Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression

et al. 2016

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurones, which leads to paralysis and death in an average of 3 years following diagnosis. The cause of ALS is unknown, but there is substantial evidence that metabolic factors, including nutritional state and body weight, affect disease progression and survival. This review provides an overview of the characteristics of metabolic dysregulation in ALS focusing on mechanisms that lead to disrupted energy supply (at a whole-body and cellular level) and altered energy expenditure. We discuss how a decrease in energy supply occurs in parallel with an increase in energy demand and leads to a state of chronic energy deficit which has a negative impact on disease outcome in ALS. We conclude by presenting potential and tested strategies to compensate for, or correct this energy imbalance, and speculate on promising areas for further research.

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“…However, localization with other proteins that form cytoplasmic inclusions during ALS was not investigated. Mutant TDP-43 has been shown to induce oxidative stress and subsequent nuclear accumulation of NRF2 in cell culture, while motor cortexes from TDP-43 A315T transgenic mice show significant increases in the levels of the NRF2 target HO-1 (33,34). These data indicated that there is a deregulation of the linear KEAP1/NRF2/ARE pathway in ALS, a deregulation associated with the sequestering of KEAP1 in ubiquitinated pathological inclusions and poor induction of cytoprotective ARE gene products.…”

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confidence: 96%

RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

Bakkar

Kousari

Kovalik

et al. 2015

Molecular and Cellular Biology

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons. Various factors contribute to the disease, including RNA binding protein dysregulation and oxidative stress, but their exact role in pathogenic mechanisms remains unclear. We have recently linked another RNA binding protein, RBM45, to ALS via increased levels of protein in the cerebrospinal fluid of ALS patients and its localization to cytoplasmic inclusions in ALS motor neurons. Here we show RBM45 nuclear exit in ALS spinal cord motor neurons compared to controls, a phenotype recapitulated in vitro in motor neurons treated with oxidative stressors. We find that RBM45 binds and stabilizes KEAP1, the inhibitor of the antioxidant response transcription factor NRF2. ALS lumbar spinal cord lysates similarly show increased cytoplasmic binding of KEAP1 and RBM45. Binding of RBM45 to KEAP1 impedes the protective antioxidant response, thus contributing to oxidative stress-induced cellular toxicity. Our findings thus describe a novel link between a mislocalized RNA binding protein implicated in ALS (RBM45) and dysregulation of the neuroprotective antioxidant response seen in the disease.A myotrophic lateral sclerosis (ALS) is a fatal idiopathic adultonset neurodegenerative disease characterized by a loss of motor neurons in the brain, brain stem, and spinal cord, with consequent atrophy of associated muscles (1, 2). Incidence rates are 1 to 3 cases per 100,000 individuals per year. Pathogenic mechanisms underlying the disease are not fully understood. Approximately 5 to 10% of all ALS cases are familial (3), with the remaining cases being termed sporadic, contributing to the clinical heterogeneity within the patient population. Nevertheless, typical hallmarks of ALS include neuronal atrophy, mitochondrial dysfunction, excitotoxicity, oxidative stress, and ubiquitinated cellular inclusions (4, 5). A growing number of genes with diverse functions have been implicated in the disease etiology. Mutations in a number of RNA binding proteins have been linked to ALS, including TAR DNA binding protein 43 (TDP-43) and Fused in Sarcoma (FUS) (6). Mutations in these genes result in reduced levels in the nucleus and their accumulation in cytoplasmic ubiquitin-positive inclusions (7). Both TDP-43 and FUS possess prion-like domains and relocate to cytoplasmic stress granules under stress conditions, suggesting potential pathology commonalities (8). Genetic alterations in these and other RNA binding proteins link RNA metabolism to the pathobiology of ALS.Recently, we linked another RNA binding protein, RBM45, to ALS using a proteomic screen of cerebrospinal fluid (CSF) from ALS and control subjects (9). RBM45, also known as Drb1, was first identified as a novel RNA binding protein that functions in neural development (10). RBM45 possesses three RNA recognition motifs (RRMs) as well as a C-terminal nuclear localization sequence (10). By using a large liquid chromatography-tandem mass spectrometry (LC-MS/MS) unbia...

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HO-1 induction in motor cortex and intestinal dysfunction in TDP-43 A315T transgenic mice

Cited by 65 publications

References 25 publications

Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression

RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

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