TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis

Guise, Amanda J.; Misal, Santosh A.; Carson, Richard; Chu, Jen-Hwa; Boekweg, Hannah; Van Der Watt, Daisha; Welsh, Nora C.; Truong, Thy; Liang, Yiran; Xu, Shanqin; Benedetto, Gina; Gagnon, Jake; Payne, Samuel H.; Plowey, Edward D.; Kelly, Ryan T.

doi:10.1016/j.celrep.2023.113636

Cited by 12 publications

(26 citation statements)

References 98 publications

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“…Indeed, several studies have reported increased levels of USP10 in some types of cancer including glioblastoma (Grunda et al, 2006), as well as in affected neurons in PD (Takahashi et al, 2018). Interestingly, very recently, USP10 protein levels have been found to be inversely correlated with TDP-43 pathological burden in postmortem human motor neurons (Guise et al, 2024). Altogether, these results clearly show that USP10 is affected in TDP-43 proteinopathies.…”

Section: Discussionmentioning

confidence: 99%

A functional interaction between TDP-43 and USP10 reveals USP10 dysfunction in TDP-43 proteinopathies

Marrero-Gagliardi,

Noda,

Zanovello

et al. 2024

Preprint

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by the progressive degeneration of motor neurons in the cerebral cortex and spinal cord, with a rapid progression from diagnosis to death. The great majority of ALS cases and around 50% of FTD cases present with TDP-43 pathology, leading to mislocalization and cytoplasmic aggregation of TDP-43, which can result in both its loss of nuclear functions and a gain of toxicity in the cytoplasm. TDP-43 and other RNA-binding proteins accumulate in stress granules (SGs) under stress conditions. The ubiquitin-specific protease 10 (USP10) is an inhibitor of SGs assembly that has been recently linked to neurodegeneration. Here, we identified a new functional interaction between TDP-43 and USP10, in which USP10 can control multiple aspects of TDP-43 biology that are thought to play important roles in its involvement in disease pathogenesis, such as its cytoplasmic and nuclear aggregation, expression and splicing functionality. In turn, TDP-43 is also able to control diverse aspects of USP10 biology, such as its expression levels, aggregation and function. Critically, we found USP10 dysregulation in ALS and FTD patients, overall suggesting a possible role for USP10 in ALS/FTD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

A functional interaction between TDP-43 and USP10 reveals USP10 dysfunction in TDP-43 proteinopathies

Marrero-Gagliardi,

Noda,

Zanovello

et al. 2024

Preprint

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“…On a cellular level, 97% of ALS patients have abnormal ubiquitinated protein aggregates of TAR DNA-binding protein 43 (TDP43) in neuronal cytoplasm [41][42][43]. This mislocalization of TDP43 from the nucleus to the cytoplasm has been associated with impaired ribosomal function, altered RNA translation, aberrant splicing, and cryptic peptide formation [42][43][44]. These cryptic peptides can insert themselves into the sequence of what would otherwise be properly translated proteins, impeding normal function [42][43][44].…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

“…This mislocalization of TDP43 from the nucleus to the cytoplasm has been associated with impaired ribosomal function, altered RNA translation, aberrant splicing, and cryptic peptide formation [42][43][44]. These cryptic peptides can insert themselves into the sequence of what would otherwise be properly translated proteins, impeding normal function [42][43][44]. Beyond impaired TDP43 localization, motor neurons in ALS patients have disrupted mitochondrial respiration, elevated levels of oxidative stress, and increased glutamatergic neurotoxicity [44,45].…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

“…These cryptic peptides can insert themselves into the sequence of what would otherwise be properly translated proteins, impeding normal function [42][43][44]. Beyond impaired TDP43 localization, motor neurons in ALS patients have disrupted mitochondrial respiration, elevated levels of oxidative stress, and increased glutamatergic neurotoxicity [44,45]. A combination of established and novel changes occurring during ALS with the resulting biomarkers across multiple sample types are shown in Figure 2.…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

“…Stathmin-2 (STMN2), for example, is a protein partially regulated by TDP43 that repairs damaged axons and guides neural regrowth following damage. This protein is frequently mis-spliced in ALS patients, which coincides with reduced levels of canonical STMN2 and increased vulnerability to neurodegeneration [44,54,55].…”

Section: Tdp43mentioning

confidence: 99%

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Cheslow,

Snook,

Waldman

2024

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Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track responses to therapy, and parse the causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD).

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Single‐cell proteomics (SCP) has advanced significantly in recent years, with new tools specifically designed for the preparation and analysis of single cells now commercially available to researchers. The field is sufficiently mature to be broadly accessible to any lab capable of isolating single cells and performing bulk‐scale proteomic analyses. In this review, we highlight recent work in the SCP field that has significantly lowered the barrier to entry, thus providing a practical guide for those who are newly entering the SCP field. We outline the fundamental principles and report multiple paths to accomplish the key steps of a successful SCP experiment including sample preparation, separation, and mass spectrometry data acquisition and analysis. We recommend that researchers start with a label‐free SCP workflow, as achieving high‐quality and quantitatively accurate results is more straightforward than label‐based multiplexed strategies. By leveraging these accessible means, researchers can confidently perform SCP experiments and make meaningful discoveries at the single‐cell level.

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TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis

Cited by 12 publications

References 98 publications

A functional interaction between TDP-43 and USP10 reveals USP10 dysfunction in TDP-43 proteinopathies

A functional interaction between TDP-43 and USP10 reveals USP10 dysfunction in TDP-43 proteinopathies

Biomarkers for Managing Neurodegenerative Diseases

Review and Practical Guide for Getting Started With Single‐Cell Proteomics

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