A motor neuron strategy to save time and energy in neurodegeneration: adaptive protein stoichiometry

Zucchi, Elisabetta; Lu, Ching‐Hua; Cho, Yunju; Chang, Rakwoo; Adiutori, Rocco; Zubiri, Irene; Ceroni, Mauro; Cereda, Cristina; Pansarasa, Orietta; Greensmith, Linda; Malaspina, Andrea; Petzold, Axel

doi:10.1111/jnc.14542

Cited by 27 publications

(32 citation statements)

References 74 publications

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“…Interestingly, alterations in NF stoichiometry have been reproduced in animal models by overexpressing one subunit over the others, resulting in axonal swellings and progressive neuropathic changes highly reminiscent of ALS pathological changes [38,39]. On the other hand, modifications in NF stoichiometry might also be an adaptive strategy to save energy in the degenerating motor neuron, as other studies suggest [40]. Further longitudinal studies on NF stoichiometry from the presymptomatic phase to the onset and progression of the disease in animal models and human subjects carrying different disease associated genemutations would be helpful to untangle these structural aspects.…”

Section: Nf Structure and Compositionmentioning

confidence: 98%

“…Additionally, different NF trajectories might occur according to the disease progression rate [82], suggesting that the pace of neuroaxonal damage varies according to the extent of neurodegeneration. Finally, it has been speculated that the occurrence of adaptive phenomena as transcriptional or translational modifications of NF subunits may imply a compensatory over-expression of NfL over the other isoforms within the degenerating motor neuron in order to save energy [40].…”

Section: Limitations and Future Directionsmentioning

confidence: 99%

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Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

Zucchi

Bonetto

Sorarù

et al. 2020

Mol Neurodegeneration

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Motor neuron diseases (MNDs) are etiologically and biologically heterogeneous diseases. The pathobiology of motor neuron degeneration is still largely unknown, and no effective therapy is available. Heterogeneity and lack of specific disease biomarkers have been appointed as leading reasons for past clinical trial failure, and biomarker discovery is pivotal in today’s MND research agenda. In the last decade, neurofilaments (NFs) have emerged as promising biomarkers for the clinical assessment of neurodegeneration. NFs are scaffolding proteins with predominant structural functions contributing to the axonal cytoskeleton of myelinated axons. NFs are released in CSF and peripheral blood as a consequence of axonal degeneration, irrespective of the primary causal event. Due to the current availability of highly-sensitive automated technologies capable of precisely quantify proteins in biofluids in the femtomolar range, it is now possible to reliably measure NFs not only in CSF but also in blood. In this review, we will discuss how NFs are impacting research and clinical management in ALS and other MNDs. Besides contributing to the diagnosis at early stages by differentiating between MNDs with different clinical evolution and severity, NFs may provide a useful tool for the early enrolment of patients in clinical trials. Due to their stability across the disease, NFs convey prognostic information and, on a larger scale, help to stratify patients in homogenous groups. Shortcomings of NFs assessment in biofluids will also be discussed according to the available literature in the attempt to predict the most appropriate use of the biomarker in the MND clinic.

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Section: Nf Structure and Compositionmentioning

confidence: 98%

Section: Limitations and Future Directionsmentioning

confidence: 99%

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

Zucchi

Bonetto

Sorarù

et al. 2020

Mol Neurodegeneration

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“…110 Affected neurons in ALS have altered metabolism that results in a decreased production of NfH versus NfL. 111 This alters the normal stoichiometry of the three neurofilament proteins from 7:3:2 (NfL:Neurofilament Medium Chain (NfM):NfH, respectively) to 24:2.4:1.6 (NfL:NfM: NfH) 111 and can be found accumulated as aggregate in the motor neurons. 112 This is a further explanation for increased NfL levels.…”

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confidence: 99%

Blood neurofilament light: a critical review of its application to neurologic disease

Barro

Chitnis

Weiner

2020

Ann Clin Transl Neurol

181

163

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Neuronal injury is a universal event that occurs in disease processes that affect both the central and peripheral nervous systems. A blood biomarker linked to neuronal injury would provide a critical measure to understand and treat neurologic diseases. Neurofilament light chain (NfL), a cytoskeletal protein expressed only in neurons, has emerged as such a biomarker. With the ability to quantify neuronal damage in blood, NfL is being applied to a wide range of neurologic conditions to investigate and monitor disease including assessment of treatment efficacy. Blood NfL is not specific for one disease and its release can also be induced by physiological processes. Longitudinal studies in multiple sclerosis, traumatic brain injury, and stroke show accumulation of NfL over days followed by elevated levels over months. Therefore, it may be hard to determine with a single measurement when the peak of NfL is reached and when the levels are normalized. Nonetheless, measurement of blood NfL provides a new blood biomarker for neurologic diseases overcoming the invasiveness of CSF sampling that restricted NfL clinical application. In this review, we examine the use of blood NfL as a biologic test for neurologic disease.

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“…Standards, primary and secondary Abs, detection range including lower and upper limits of detection were specified in the manufacturer’s conditions of the commercial assays. Analysis of Nf‐M protein isoform was not attempted as currently available immunoassays have not been extensively tested in ALS 23 …”

Section: Methodsmentioning

confidence: 99%

Humoral response to neurofilaments and dipeptide repeats in ALS progression

Puentes

Lombardi

et al. 2021

Ann Clin Transl Neurol

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Objective To appraise the utility as biomarkers of blood antibodies and immune complexes to neurofilaments and dipeptide repeat proteins, the products of translation of the most common genetic mutation in amyotrophic lateral sclerosis (ALS). Methods Antibodies and immune complexes against neurofilament light, medium, heavy chains as well as poly‐(GP)‐(GR) dipeptide repeats were measured in blood samples from the ALS Biomarkers (n = 107) and the phenotype–genotype biomarker (n = 129) studies and in 140 healthy controls. Target analyte levels were studied longitudinally in 37 ALS cases. Participants were stratified according to the rate of disease progression estimated before and after baseline and C9orf72 genetic status. Survival and longitudinal analyses were undertaken with reference to matched neurofilament protein expression. Results Compared to healthy controls, total neurofilament proteins and antibodies, neurofilament light immune complexes (p < 0.0001), and neurofilament heavy antibodies (p = 0.0061) were significantly elevated in ALS, patients with faster progressing disease (p < 0.0001) and in ALS cases with a C9orf72 mutation (p < 0.0003). Blood neurofilament light protein discriminated better ALS from healthy controls (AUC: 0.92; p < 0.0001) and faster from slower progressing ALS (AUC: 0.86; p < 0.0001) compared to heavy‐chain antibodies and light‐chain immune complexes (AUC: 0.79; p < 0.0001 and AUC: 0.74; p < 0.0001). Lower neurofilament heavy antibodies were associated with longer survival (Log‐rank Chi‐square: 7.39; p = 0.0065). Increasing levels of antibodies and immune complexes between time points were observed in faster progressing ALS. Conclusions We report a distinctive humoral response characterized by raising antibodies against neurofilaments and dipeptide repeats in faster progressing and C9orf72 genetic mutation carriers ALS patients. We confirm the significance of plasma neurofilament proteins in the clinical stratification of ALS.

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A motor neuron strategy to save time and energy in neurodegeneration: adaptive protein stoichiometry

Cited by 27 publications

References 74 publications

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

Blood neurofilament light: a critical review of its application to neurologic disease

Humoral response to neurofilaments and dipeptide repeats in ALS progression

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