Proteomic investigation of ALS motor cortex identifies known and novel pathogenetic mechanisms

Lee, Aven; Henderson, Robert D.; Arachchige, Buddhika J.; Robertson, Thomas; McCombe, Pamela A.

doi:10.1016/j.jns.2023.120753

Cited by 4 publications

(2 citation statements)

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“…Attempts to determine the presence of TDP-43 in SG fractions isolated from tissues is limited and may lack specificity due to TDP-43 immunoprecipitation from soluble and not insoluble fractions (Montalbano et al, 2020). Proteomics analysis has been performed to observe changes in postmortem frozen motor cortex samples form ALS donors compared with healthy control samples (Lee et al, 2023) as well as longitudinal analysis in cortex samples from NEFH-TDP-43 mice (San Gil et al, 2024). These studies identified multiple disease-related changes in biological pathways.…”

Section: Introductionmentioning

confidence: 99%

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Proteomic analysis of the TDP-43-associated insoluble fraction from NEFH-TDP-43 mouse brain suggests sustained stress granule formation, CLUH granule recruitment and impaired mitochondrial metabolism

Dunlop,

Mason,

Tsitkanou

et al. 2024

Preprint

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Cytoplasmic accumulation and aggregation of TDP-43 is a hallmark of ~97% of ALS cases. Formation of TDP-43 insoluble aggregates is suggested to either directly or indirectly cause motor neurone loss and progressive neuromuscular degeneration, although how this occurs is not precisely understood. Cytoplasmic TDP-43 is observed in stress granules (SG). SGs are ribonucleoprotein (RNP) complexes formed during stress conditions, consisting of mRNAs and RNA-binding proteins (RNPs). Chronic TDP-43/SG formation may play a role in neuromuscular degeneration in ALS. The composition of in vivo TDP-43-asscociated SGs in ALS not known. This knowledge may provide insights into the molecular pathways impaired by TDP-43-associated SGs and suggest disease modifying mechanisms. The aim of this study was to isolate and analyse the proteome of the insoluble TDP-43-associated SG fraction from brain tissue of end-stage TDP-43∆NLS mice. Proteomic analysis identified 134 enriched and 17 depleted proteins in the TDP-43∆NLS mice, when compared to the control mice. Bioinformatics analyses of the impacted proteins from the SG preparation suggested that brain tissue from end-stage NEFH-TDP-43∆NLS mice have sustained SG formation, CLUH granule recruitment and impaired mitochondrial metabolism. This is the first time that CLUH granule recruitment has been demonstrated in ALS and the known role of CLUH suggests that cell starvation is a potential mechanism of motor neurone loss that could be targeted in ALS.

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Section: Introductionmentioning

confidence: 99%

“…These studies identified multiple disease-related changes in biological pathways. However, these analyses were performed using soluble protein fractions (Lee et al, 2023; San Gil et al, 2024) without TDP-43 immunoprecipitation, and would therefore not accurately capture the TDP-43-associated SG proteome.…”

Section: Introductionmentioning

confidence: 99%