2022
DOI: 10.1002/cjp2.297
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pTDP‐43 aggregates accumulate in non‐central nervous system tissues prior to symptom onset in amyotrophic lateral sclerosis: a case series linking archival surgical biopsies with clinical phenotypic data

Abstract: Neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) are traditionally considered strictly neurological disorders. However, clinical presentation is not restricted to neurological systems, and non-central nervous system (CNS) manifestations, particularly gastrointestinal (GI) symptoms, are common. Our objective was to understand the systemic distribution of pathology in archived non-CNS tissues, taken as part of routine clinical practice… Show more

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Cited by 14 publications
(9 citation statements)
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“…Indeed, TDP-43 depletion in mouse Schwann cells showed that TDP-43 regulates the inclusion of a cell-type specific cryptic exon in Neurofascin in these cells, highlighting how, if certain TDP-43 cryptic exons are expressed only by given cells, they could allow tracing of TDP-43 proteinopathy. Furthermore, recent work showing that pTDP-43 and loss of nuclear TDP-43 can be detected years before ALS disease presentation in central nervous system and non-central nervous system tissue suggests that detection of TDP-43 cryptic exons could possibly pre-date disease onset [64,65].…”
Section: Opportunities For Novel Biomarkersmentioning
confidence: 99%
“…Indeed, TDP-43 depletion in mouse Schwann cells showed that TDP-43 regulates the inclusion of a cell-type specific cryptic exon in Neurofascin in these cells, highlighting how, if certain TDP-43 cryptic exons are expressed only by given cells, they could allow tracing of TDP-43 proteinopathy. Furthermore, recent work showing that pTDP-43 and loss of nuclear TDP-43 can be detected years before ALS disease presentation in central nervous system and non-central nervous system tissue suggests that detection of TDP-43 cryptic exons could possibly pre-date disease onset [64,65].…”
Section: Opportunities For Novel Biomarkersmentioning
confidence: 99%
“…This raises the question of how pathology arising in the gut could reach the CNS, or even if this event would occur at the same time in both locations. The presence of pTDP-43 aggregates within intestinal tissues suggests the possibility of a similar mechanism of pathological spread to that observed in other neurodegenerative diseases [ 67 ]. Dysbiosis may induce neurodegeneration of the neurons of the enteric nervous system.…”
Section: Pathogenic Risk Factors Involved In Alsmentioning
confidence: 79%
“…The cytoplasmic accumulation of phosphorylated TDP-43 (pTDP-43) aggregates in the CNS [ 64 ] of sporadic ALS (sALS) and most genetic ALS cases have been demonstrated within muscle [ 65 ] and peripheral nerve biopsies [ 66 ]. Surprisingly, a recent study on colonic biopsies [ 67 ] has also shown evidence of aggregation of pTDP-43 within the lamina propria (the mucosal connective tissue deep to the surface enterocytes) and the myenteric plexus. This raises the question of how pathology arising in the gut could reach the CNS, or even if this event would occur at the same time in both locations.…”
Section: Pathogenic Risk Factors Involved In Alsmentioning
confidence: 99%
“…A study performed in Sweden established that individuals exhibiting gastrointestinal symptoms but with normal colonoscopy and histologically normal biopsy findings had an increased risk of developing ALS later in life . This evidence was supported by a study which established the manifestation of neurotoxic pTDP-43 protein aggregates in the GI tract before diagnosis of ALS and, in some cases, even before appearance of CNS symptoms (Pattle et al, 2022). In addition to the role of gut pathology in ALS, the literature also provides evidence for the influence of gut microbiota.…”
Section: Introduction Introductionmentioning
confidence: 78%