Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers

Akiyama, Tetsuya; Koike, Yasuhiro; Petrucelli, Leonard; Gitler, Aaron D.

doi:10.1002/ctm2.818

Cited by 14 publications

(12 citation statements)

References 64 publications

(148 reference statements)

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“…TDP-43 represses cryptic exon inclusion in Stathmin-2 (STMN-2) through its binding site in the first intron, but when pathologically mislocalized, TDP-43 fails to repress the incorporation of cryptic exon 2A into mature mRNA 5 . Truncated STMN-2 mRNA subsequently arises because of a premature polyadenylation signal in cryptic exon 2A itself [6][7][8] . Thus, detection of this incorrectly spliced STMN-2 cryptic exon is a sensitive molecular marker of TDP-43 loss-offunction.…”

Section: Introductionmentioning

confidence: 99%

RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides withSTMN-2cryptic splicing and precedes clinical manifestation in ALS

Spence,

Waldron,

Saleeb

et al. 2023

Preprint

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TDP-43 is an aggregation-prone protein which accumulates in the hallmark pathological inclusions of amyotrophic lateral sclerosis (ALS). However, analysis of deeply-phenotyped human post-mortem samples has shown that TDP-43 aggregation, revealed by standard antibody methods, correlates poorly with symptom manifestation. Recent identification of cryptic-splicing events, such as the detection of Stathmin-2 (STMN-2) cryptic exons, are providing evidence implicating TDP-43 loss-of-function as a potential driving pathomechanism, but the temporal nature of TDP-43 loss and its relation to the disease process and clinical phenotype is not known. To address these outstanding questions, we used a novel RNA aptamer, TDP-43APT, to detect TDP-43 aggregation and used single molecule in situ hybridization to sensitively reveal TDP-43 loss-of-function and applied these in a deeply-phenotyped human post-mortem tissue cohort. We demonstrate that TDP-43APT identifies pathological TDP-43, detecting aggregation events that cannot be detected by classical antibody stains. We show that nuclear TDP-43 pathology is an early event, occurring prior to cytoplasmic aggregation and is associated with loss-of-function measured by coincident STMN-2 cryptic splicing pathology. Crucially, we show that these pathological features of TDP-43 loss-of-function precede the clinical inflection point and are not required for region specific clinical manifestation. Furthermore, we demonstrate that gain-of-function in the form of extensive cytoplasmic aggregation, but not loss-of-function, is the primary molecular correlate of clinical manifestation. Taken together, our findings demonstrate implications for early diagnostics as the presence of STMN-2 cryptic exons and early TDP-43 aggregation events could be detected prior to symptom onset, holding promise for early intervention in ALS.

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Section: Introductionmentioning

confidence: 99%

RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides withSTMN-2cryptic splicing and precedes clinical manifestation in ALS

Spence,

Waldron,

Saleeb

et al. 2023

Preprint

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“…If the effect of CD36 on the actions of protein aggregates prove to be more common and involve other protein aggregates in addition to those of α-synuclein, the studies should extend to a broader range of neurological diseases. These should include fronto-temporal dementia and the closely related motor neuron disease (amyotrophic lateral sclerosis), where protein aggregates also occur 74 , but the key mechanisms leading to the loss of neurons remain poorly understood despite the identification of several molecules of interest 75 – 78 .…”

Section: Discussionmentioning

confidence: 99%

Six genetically linked mutations in the CD36 gene significantly delay the onset of Alzheimer's disease

Šerý

Zeman

Sheardová

et al. 2022

Sci Rep

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The risk of Alzheimer’s disease (AD) has a strong genetic component, also in the case of late-onset AD (LOAD). Attempts to sequence whole genome in large populations of subjects have identified only a few mutations common to most of the patients with AD. Targeting smaller well-characterized groups of subjects where specific genetic variations in selected genes could be related to precisely defined psychological traits typical of dementia is needed to better understand the heritability of AD. More than one thousand participants, categorized according to cognitive deficits, were assessed using 14 psychometric tests evaluating performance in five cognitive domains (attention/working memory, memory, language, executive functions, visuospatial functions). CD36 was selected as a gene previously shown to be implicated in the etiology of AD. A total of 174 polymorphisms were tested for associations with cognition-related traits and other AD-relevant data using the next generation sequencing. Several associations between single nucleotide polymorphisms (SNP’s) and the cognitive deficits have been found (rs12667404 with language performance, rs3211827 and rs41272372 with executive functions, rs137984792 with visuospatial performance). The most prominent association was found between a group of genotypes in six genetically linked and the age at which the AD patients presented with, or developed, a full-blown dementia. The identified alleles appear to be associated with a delay in the onset of LOAD. In silico studies suggested that the SNP’s alter the expression of CD36 thus potentially affecting CD36-related neuroinflammation and other molecular and cellular mechanisms known to be involved in the neuronal loss leading to AD. The main outcome of the study is an identification of a set of six new mutations apparently conferring a distinct protection against AD and delaying the onset by about 8 years. Additional mutations in CD36 associated with certain traits characteristic of the cognitive decline in AD have also been found.

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“…Although TDP-43 is an RNA/DNA binding protein that physiologically resides in the nucleus, hyperphosphorylated extranuclear inclusions are found in neuronal cells of approximately 45% of patients with FTD and approximately 97% of patients with ALS ( Ling et al., 2013 ; Neumann et al., 2006 ). Loss of nuclear TDP-43 results in defective splicing of several transcripts, among which the most thoroughly described is the cryptic splicing of Stathmin 2 ( STMN2 ), a neuron-specific gene important for neuronal survival ( Akiyama et al., 2022 ; Klim et al., 2019 ; Melamed et al., 2019 ; Prudencio et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology

et al. 2023

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Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers

Cited by 14 publications

References 64 publications

RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides withSTMN-2cryptic splicing and precedes clinical manifestation in ALS

RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides withSTMN-2cryptic splicing and precedes clinical manifestation in ALS

Six genetically linked mutations in the CD36 gene significantly delay the onset of Alzheimer's disease

Granulin loss of function in human mature brain organoids implicates astrocytes in TDP-43 pathology

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