Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis

Kirby, Janine; Goodall, Gerald; Smith, William R.; Highley, J. Robin; Masanzu, Rudo; Hartley, Judith; Hibberd, Rachel; Hollinger, Hannah; Wharton, Stephen B.; Morrison, Karen; Ince, Paul G.; McDermott, Christopher J.; Shaw, Pamela J.

doi:10.1007/s10048-009-0218-9

Cited by 74 publications

(37 citation statements)

References 35 publications

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“…Because significant neuronal loss was only seen in brain neurons but not in spinal cord motor neurons, it appeared that behavior deficits in hemizygous TDP-43 M337V mice, including poor rotarod or beam-walking performance, were likely caused by dysfunction or loss of brain neurons rather than spinal cord motor neurons. Although some studies showed the absence of dementia in patients bearing the M337V mutation, 7,25 one study from Kirby et al 26 reported intellectual impairment in a patient from a family bearing the M337V mutant with very early disease onset at 2.5 years of age. In fact, some TDP-43 mutations have been identified in FTD patients without motor neuron disease.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…From the data available, it is evident that combining different MR imaging modalities that are sensitive to different aspects of ALS pathology (eg, motor and extramotor) is a promising way to further increase our understanding of the mechanisms accounting for the accumulation of irreversible disability in this condition. Moreover, the emerging scenario from genetic studies indicates a consistent overlap between the pathogenetic changes in most forms of sporadic and familial ALS, [108][109][110] thus suggesting that the application of neuroimaging in familial patients with ALS may allow identification of abnormalities that can hopefully be translated to the assessment of sporadic ALS.…”

Section: Discussionmentioning

confidence: 99%

The Present and the Future of Neuroimaging in Amyotrophic Lateral Sclerosis

Agosta¹,

Chiò²,

Cosottini³

et al. 2010

AJNR Am J Neuroradiol

117

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SUMMARY:In patients with ALS, conventional MR imaging is frequently noninformative, and its use has been restricted to excluding other conditions that can mimic ALS. Conversely, the extensive application of modern MR imagingϪbased techniques to the study of ALS has undoubtedly improved our understanding of disease pathophysiology and is likely to have a role in the identification of potential biomarkers of disease progression. This review summarizes how new MR imaging technology is changing dramatically our understanding of the factors associated with ALS evolution and highlights the reasons why it should be used more extensively in studies of disease progression, including clinical trials.ABBREVIATIONS: ALS ϭ amyotrophic lateral sclerosis; ALSFRS ϭ ALS Functional Rating Scale; Cho ϭ choline; Cr ϭ creatine; CST ϭ corticospinal tract; DTI ϭ diffusion tensor imaging; FA ϭ fractional anisotropy; FLAIR ϭ fluid-attenuated inversion recovery; fMRI ϭ functional MR imaging; FTD ϭ frontotemporal dementia; FUS/TLS ϭ fused in sarcoma/translocated in liposarcoma gene; GM ϭ gray matter; 1 H-MR spectroscopy ϭ proton MR spectroscopy; L ϭ left; LMN ϭ lower motor neuron; MD ϭ mean diffusivity; mIns ϭ myo-inositol; MT ϭ magnetization transfer; MTR ϭ MT ratio; NAA ϭ N-acetylaspartate; ns ϭ not significant; PD ϭ proton density; R ϭ right; SOD1 ϭ superoxide dismutase 1; SPM ϭ statistical parametric mapping; TDP-43 ϭ TAR DNA-binding protein gene; UMN ϭ upper motor neuron; VBM ϭ voxel-based morphometry; WM ϭ white matter A LS, also known as motor neuron disease, is a neurodegenerative disorder characterized by a progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, brain stem, and spinal cord. The phenotypic expression of ALS is highly heterogeneous and determined by 4 elements: 1) body region of onset, 2) relative mix of UMN and LMN involvement, 3) rate of progression, and 4) cognitive impairment.1 In approximately 5%-10% of patients, the disease is inherited; 20% of these individuals have a mutation of the SOD1 gene; approximately 2%-5%, of the TARDBP (TDP-43) gene; and 2%-4%, of the FUS/TLS gene. 2Most patients with ALS, however, have no obvious family history and have sporadic ALS.2 To date, the only specific marker of sporadic ALS is the presence of inclusions staining positively for ubiquitin and TDP-43 in degenerating motor neurons. 3Despite technical advances in medicine in the last century, the diagnosis of sporadic ALS relies on the interpretation of clinical symptoms and signs (ie, signs suggestive of combined UMN and LMN degeneration, together with disease progression compatible with a neurodegenerative disorder). Paraclinical and laboratory tests are used only to exclude "ALS-mimic" syndromes. 4,5 In ALS, the absence of a disease marker for UMN and LMN involvement has 2 main negative consequences. First, the delay from onset of the disease to diagnosis of ALS can vary between 13 and 18 months 6,7

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“…Mutations of TARDBP have been identified as a disease protein in ubiquitin-positive, τ-, and α-synuclein-negative frontotemporal dementia (FTLD-U) and in amyotrophic lateral sclerosis (ALS) [2,3]. Over the past years, 44 mutations in TARDBP have been reported in 5% of non- SOD1 familial ALS (FALS) and 0.4% of sporadic ALS (SALS) [4,5] and, more rarely, in cases with frontotemporal dementia (FTD) [6], Parkinson's disease [7] and Alzheimer's disease [8]. Most of the reported mutations are missense mutations that occur in the highly conserved C-terminus of TARDBP , which encodes the exon 6 [9].…”

Section: Introductionmentioning

confidence: 99%

“…Phenotypically, ALS patients with TARDBP mutations may present with limb or bulbar onset [12,13]. There is however considerable variation in age of onset and rapidity of disease course [4]. …”

Section: Introductionmentioning

confidence: 99%

Phenotypes in Swiss Patients with Familial ALS Carrying <b><i>TARDBP</i></b> Mutations

et al. 2013

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Background: Recently, mutations in the TARDBP gene encoding the TAR DNA-binding protein 43 (TDP-43) have been identifiedin some familial amyotrophic lateral sclerosis (ALS) and sporadic ALS patients. The phenotype and frequency of TARDBP mutation carriers reportedly varies greatly among European populations. Objective: To define the phenotypic spectrum of TARDBP mutations and their frequency in a Swiss population. Methods: A total of 225 patients diagnosed with ALS (182 sporadic cases, 43 familial cases) were screened for TARDBP mutations. All patients were carefully examined and interviewed for a familial predisposition. Except for 1 patient who was followed at the University of Geneva, all patients were followed at the Kantonsspital St. Gallen. Results: 43 patients (19.5%) had a definite family history for ALS. A TARDBP mutation was identified in 4 of these (9.3%). Two female ALS patients carried the p.Asn352Ser mutation. Both had limb onset and a slowly progressive course of the disease. A novel mutation (p.Gly376Asp) was identified in a 44-year-old female patient. Survival amongst affected family members varied between 6 and 18 months. The patient and also the other siblings affected with ALS had an accessory nipple. A fourth male patient carried the p.Ala90Val mutation. None of the patients had overt cognitive impairment. TARDBP mutations were not found among patients with sporadic forms of ALS. Conclusion: In this Swiss population, the frequency of familial ALS is higher than reported earlier in other populations. The novel p.Gly376Asp TARDBP mutation is associated with rapid disease progression and may be associated with an accessory nipple while the p.Asn352Ser mutation is associated with slow disease progression.

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Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis

Cited by 74 publications

References 35 publications

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

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

The Present and the Future of Neuroimaging in Amyotrophic Lateral Sclerosis

Phenotypes in Swiss Patients with Familial ALS Carrying <b><i>TARDBP</i></b> Mutations

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