TDP‐43 neuropathology is similar in sporadic amyotrophic lateral sclerosis with or without <i>TDP‐43</i> mutations

Pamphlett, Roger; Luquin, Natasha; McLean, Catriona; Jew, Stephen Kum; Adams, Lorel

doi:10.1111/j.1365-2990.2008.00982.x

Cited by 41 publications

(12 citation statements)

References 12 publications

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“…Pathological studies in the few available cases [4,17] and in transgenic models [18,19] did not specifically examine dorsal root ganglia, although TDP-43 is normally expressed in sensory neuron nuclei [20]. On the patient's nerve biopsy, no abnormal accumulation of TDP-43 was found in peripheral axons, in keeping with the fact that, in the central nervous system of patients with TARDBP mutations or sporadic ALS, the protein does not accumulate in axons, but in the neuron cell body and dendrites [1,4]. …”

Section: Discussionmentioning

confidence: 99%

“…TDP-43, a protein involved in RNA processing, is thought to play a determinant role in the pathophysiology of amyotrophic lateral sclerosis (ALS), in which it is abnormally processed and sequestered in the cytoplasm, the perikaryon, and dystrophic neurites of neurons [1,2]. Variations in the TARDPB gene, which encodes TDP-43, occur in about 3% of sporadic and familial cases of ALS [3] and are mostly found in cases with a usually predominant lower motor neuron involvement and in a few patients with cognitive deficits [4-6].…”

Section: Introductionmentioning

confidence: 99%

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Sensory and motor neuronopathy in a patient with the A382P TDP-43 mutation

Camdessanché

Belzil

Jousserand

et al. 2011

Orphanet J Rare Dis

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Patients with TARDBP mutations have so far been classified as ALS, sometimes with frontal lobe dysfunction. A 66-year-old patient progressively developed a severe sensory disorder, followed by a motor disorder, which evolved over nine years. Symptoms started in the left hand and slowly involved the four limbs. Investigations were consistent with a mixed sensory and motor neuronopathy. A heterozygous change from an alanine to a proline at amino acid 382 was identified in exon 6 of the TARDPB gene (p.A382P). This case expands the phenotypic spectrum associated with mutations in the TARDBP gene and shows that sensory neurons can be severely damaged early in the course of the disease, following a propagating process, with an orderly progression from a focal starting point. A combination of severe sensory and motor neuronopathy is rarely encountered in clinical practice. The possibility of an A382P TDP-43 mutation should be considered in patients with such an association.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sensory and motor neuronopathy in a patient with the A382P TDP-43 mutation

Camdessanché

Belzil

Jousserand

et al. 2011

Orphanet J Rare Dis

View full text Add to dashboard Cite

show abstract

“…In the absence of mutation, TDP-43 pathology can be found in a majority of sporadic ALS patients with the exception of patients with SOD1 mutations (Mackenzie et al, 2007; Tan et al, 2007) and is apparently indistinguishable between patients with or without TDP-43 mutations (Pamphlett et al, 2009). Over 90% of all ALS cases exhibit TDP-43 protein pathology.…”

Section: Tdp-43 and Fus/tls Reshape Als And Ftdmentioning

confidence: 99%

Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis

Ling

Polymenidou

Cleveland

2013

Neuron

1,505

1,621

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Breakthrough discoveries identifying common genetic causes for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have transformed our view of these disorders. They share unexpectedly similar signatures, including dysregulation in common molecular players including TDP-43, FUS/TLS, ubiquilin-2, VCP, and expanded hexanucleotide repeats within the C9ORF72 gene. Dysfunction in RNA processing and protein homeostasis is an emerging theme. We present the case here that these two processes are intimately linked, with disease-initiated perturbation of either leading to further deviation of both protein and RNA homeostasis through a feed-forward loop including cell-to-cell prion-like spread that may represent the mechanism for relentless disease progression.

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“…In 2007, similar TDP-43 pathology was found also to be a prominent feature of nearly all cases of sporadic and familial IBM (Weihl et al, 2008 ; Salajegheh et al, 2009 ). Several years after the appreciation of TDP-43 pathology in ALS, FTD, and IBM, the importance of this feature was underscored by the identification of ALS-causing mutations in the gene encoding this RBP (Gitcho et al, 2008 ; Kabashi et al, 2008 ; Kuhnlein et al, 2008 ; Rutherford et al, 2008 ; Sreedharan et al, 2008 ; Van Deerlin et al, 2008 ; Yokoseki et al, 2008 ; Pamphlett et al, 2009 ). Since then, mutations impacting additional RBPs, including FUS, hnRNP A1, hnRNP A2B1, matrin-3 (MATR3), and TIA1, were identified that are causative of ALS, FTD, and/or IBM (Kwiatkowski et al, 2009 ; Vance et al, 2009 ; Kim et al, 2013 ; Liu et al, 2013 ; Johnson et al, 2014 ; Mackenzie et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Linking hnRNP Function to ALS and FTD Pathology

2018

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Following years of rapid progress identifying the genetic underpinnings of amyotrophic lateral sclerosis (ALS) and related diseases such as frontotemporal dementia (FTD), remarkable consistencies have emerged pointing to perturbed biology of heterogeneous nuclear ribonucleoproteins (hnRNPs) as a central driver of pathobiology. To varying extents these RNA-binding proteins are deposited in pathological inclusions in affected tissues in ALS and FTD. Moreover, mutations in hnRNPs account for a significant number of familial cases of ALS and FTD. Here we review the normal function and potential pathogenic contribution of TDP-43, FUS, hnRNP A1, hnRNP A2B1, MATR3, and TIA1 to disease. We highlight recent evidence linking the low complexity sequence domains (LCDs) of these hnRNPs to the formation of membraneless organelles and discuss how alterations in the dynamics of these organelles could contribute to disease. In particular, we discuss the various roles of disease-associated hnRNPs in stress granule assembly and disassembly, and examine the emerging hypothesis that disease-causing mutations in these proteins lead to accumulation of persistent stress granules.

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TDP‐43 neuropathology is similar in sporadic amyotrophic lateral sclerosis with or without TDP‐43 mutations

Cited by 41 publications

References 12 publications

Sensory and motor neuronopathy in a patient with the A382P TDP-43 mutation

Sensory and motor neuronopathy in a patient with the A382P TDP-43 mutation

Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis

Linking hnRNP Function to ALS and FTD Pathology

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