Neurofilament light chain is a promising serum biomarker in spinocerebellar ataxia type 3

Li, Quan-Fu; Dong, Yi; Yang, Lu; Xie, Juan‐Juan; Yin, Ming; Du, Yi-Chu; Cheng, Haixia; Wang, Ni; Wu, Zhi‐Ying

doi:10.1186/s13024-019-0338-0

Cited by 74 publications

(109 citation statements)

References 31 publications

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“…Nfs and mutant ataxin-3 might thus overall serve as complementary biomarkers in preclinical SCA3 mouse treatment trials. Taken together, these comprehensive findings of our study largely extend recent preliminary findings from our and other labs (Wilke et al, 2018;Li et al, 2019) which suggested NfL increases in human SCA3, but were limited to non-multicentric, single-assay, human-only NfL studies, which also lacked the comparative assessment of NfL and pNfH and the biomarker cascade mapping.…”

Section: Discussionsupporting

confidence: 83%

Neurofilaments as blood biomarkers at the preataxic and ataxic stage of spinocerebellar ataxia type 3: a cross-species analysis in humans and mice

Wilke

Haas

Reetz

et al. 2019

Preprint

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Spinocerebellar ataxia type 3 (SCA3) is a devastating multisystemic neurodegenerative disease for which targeted molecular therapies are coming into reach (e.g. antisense oligonucleotides). To pave the way for upcoming translational trials, easily accessible biomarkers in SCA3 are needed, particularly for subjects at the preataxic stage and cross-validated also in animal models. We hypothesised that serum neurofilaments might serve as blood biomarkers of disease progression in both human SCA3 and mouse models, expecting increased concentrations already at the preataxic stage. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) levels were determined by ultra-sensitive single molecule array (Simoa) in cross-sectional samples of ataxic and preataxic SCA3 subjects and controls in two independent cohorts (ESMI cohort = cohort #1: n=160, EuroSCA/RiSCA cohort = cohort #2: n=89). Serum NfL and pNfH were also assessed in a 304Q SCA3 knock-in mouse model across presymptomatic and symptomatic disease stages (n=147). Ataxic SCA3 subjects showed increased serum NfL (p<0.001) and pNfH (p<0.001) levels in cohort #1, with NfL levels already increased in preataxic subjects (p<0.001). All these results were replicated in cohort #2 (all p<0.001). Cross-sectional NfL levels correlated with clinical disease severity (Scale for the Assessment and Rating of Ataxia [SARA]; r=0.43, p<0.001) and with longitudinal disease progression (annual SARA score change, ϱ=0.42, p=0.012). CAG count and age were significant predictors of individual NfL concentrations (each p<0.001). NfL levels in preataxic subjects increased with proximity to individual expected onset of ataxia (p<0.001), with significant elevations already 7.5 years before onset. Serum NfL and pNfH increases in SCA3 subjects were paralleled by similar changes in SCA3 knock-in mice, here also already starting at the presymptomatic stage and close to the onset of ataxin-3 protein increase. Serum concentrations of neurofilaments, particularly NfL, might provide easily accessible biomarkers of disease severity in both ataxic and preataxic SCA3 subjects and mice prior to conversion. Neurofilaments thus entail potential applications as progression, onset/proximity and treatment-response markers in both human and murine SCA3 trials.

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Section: Discussionsupporting

confidence: 83%

Neurofilaments as blood biomarkers at the preataxic and ataxic stage of spinocerebellar ataxia type 3: a cross-species analysis in humans and mice

Wilke

Haas

Reetz

et al. 2019

Preprint

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“…Biomarkers serve as a potential diagnostic feature in addition to providing insight into disease progression. Current biomarker candidates such as Neurofilament Light Chain are increased in ALS patients and may provide insight into disease progression, but is non-specific to ALS and only provides foresight by about 12 months before symptoms occur [269][270][271][272][273]. As TDP-43 mislocalization is a central feature in ALS and biomarkers based on phenotypes associated with mislocalization may provide the specificity and foreshadowing required for early diagnosis.…”

Section: Approaches To Study Tdp-43 Mislocalization To Better Understmentioning

confidence: 99%

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Suk

Rousseaux

2020

Mol Neurodegeneration

252

170

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Since its discovery as a primary component in cytoplasmic aggregates in post-mortem tissue of patients with Amyotrophic Lateral Sclerosis (ALS), TAR DNA Binding Protein 43 kDa (TDP-43) has remained a central focus to understand the disease. TDP-43 links both familial and sporadic forms of ALS as mutations are causative for disease and cytoplasmic aggregates are a hallmark of nearly all cases, regardless of TDP-43 mutational status. Research has focused on the formation and consequences of cytosolic protein aggregates as drivers of ALS pathology through both gainand loss-of-function mechanisms. Not only does aggregation sequester the normal function of TDP-43, but these aggregates also actively block normal cellular processes inevitably leading to cellular demise in a short time span. Although there may be some benefit to therapeutically targeting TDP-43 aggregation, this step may be too late in disease development to have substantial therapeutic benefit. However, TDP-43 pathology appears to be tightly linked with its mislocalization from the nucleus to the cytoplasm, making it difficult to decouple the consequences of nuclearto-cytoplasmic mislocalization from protein aggregation. Studies focusing on the effects of TDP-43 mislocalization have demonstrated both gain-and loss-of-function consequences including altered splicing regulation, over responsiveness to cellular stressors, increases in DNA damage, and transcriptome-wide changes. Additionally, mutations in TARDBP confer a baseline increase in cytoplasmic TDP-43 thus suggesting that small changes in the subcellular localization of TDP-43 could in fact drive early pathology. In this review, we bring forth the theme of protein mislocalization as a key mechanism underlying ALS, by highlighting the importance of maintaining subcellular proteostasis along with the gain-and loss-of-functional consequences when TDP-43 localization is dysregulated. Additional research, focusing on early events in TDP-43 pathogenesis (i.e. to the protein mislocalization stage) will provide insight into disease mechanisms, therapeutic targets, and novel biomarkers for ALS.

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“…Therefore, it is crucial that newly established biomarkers are disease specific and that there is a correlation between surrogate and clinical endpoints [16]. As for many other neurodegenerative diseases, neurofilament light chain (NfL) is shown to be increased in preataxic mutation carriers already 7.5 years before disease onset also in SCA3 even correlating with disease severity [17][18][19]. However, NfL only reflects general axonal damage which captures disease progression and disease severity and, therefore, acts as a progression and severity biomarker.…”

Section: Introductionmentioning

confidence: 99%

PolyQ-expanded ataxin-3 protein levels in peripheral blood mononuclear cells correlate with clinical parameters in SCA3: a pilot study

et al. 2020

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In view of upcoming clinical trials, quantitative molecular markers accessible in peripheral blood are of critical importance as prognostic or pharmacodynamic markers in genetic neurodegenerative diseases such as Spinocerebellar Ataxia Type 3 (SCA3), in particular for signaling target engagement. In this pilot study, we focused on the quantification of ataxin-3, the protein altered in SCA3, in human peripheral blood mononuclear cells (PBMCs) acquired from preataxic and ataxic SCA3 mutation carriers as well as healthy controls, as a molecular marker directly related to SCA3 pathophysiology. We established two different highly sensitive TR-FRET-based immunoassays to measure the protein levels of either total full-length, non-expanded and expanded, ataxin-3 or specifically polyQ-expanded ataxin-3. In PBMCs, a clear discrimination between SCA3 mutation carrier and controls were seen measuring polyQ-expanded ataxin-3 protein level. Additionally, polyQ-expanded ataxin-3 protein levels correlated with disease progression and clinical severity as assessed by the Scale for the Assessment and Rating of Ataxia. Total full-length ataxin-3 protein levels were directly influenced by the expression levels of the polyQ-expanded ataxin-3 protein, but were not correlated with clinical parameters. Assessment of ataxin-3 levels in fibroblasts or induced pluripotent stem cells allowed to distinguish mutation carriers from controls, thus providing proof-of-principle validation of our PBMC findings across cell lines. Total full-length or polyQ-expanded ataxin-3 protein was not detectable by TR-FRET assays in other biofluids like plasma or cerebrospinal fluid, indicating the need for ultra-sensitive assays for these biofluids. Standardization studies revealed that tube systems, blood sampling, and PBMC preparation may influence ataxin-3 protein levels indicating a high demand for standardized protocols in biomarker studies. In conclusion, the polyQ-expanded ataxin-3 protein is a promising candidate as a molecular target engagement marker in SCA3 in future clinical trials, determinable even in—easily accessible—peripheral blood biomaterials. These results, however, require validation in a larger cohort and further standardization of modifying conditions.

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Neurofilament light chain is a promising serum biomarker in spinocerebellar ataxia type 3

Cited by 74 publications

References 31 publications

Neurofilaments as blood biomarkers at the preataxic and ataxic stage of spinocerebellar ataxia type 3: a cross-species analysis in humans and mice

Neurofilaments as blood biomarkers at the preataxic and ataxic stage of spinocerebellar ataxia type 3: a cross-species analysis in humans and mice

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

PolyQ-expanded ataxin-3 protein levels in peripheral blood mononuclear cells correlate with clinical parameters in SCA3: a pilot study

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