Serum Creatine, Not Neurofilament Light, Is Elevated in CHCHD10-Linked Spinal Muscular Atrophy

Järvilehto, Julius; Harjuhaahto, Sandra; Palu, Edouard; Auranen, Mari; Kvist, Jouni; Zetterberg, Henrik; Koskivuori, Johanna; Lehtonen, Marko; Saukkonen, Anna Maija; Jokela, Manu; Ylikallio, Emil; Tyynismaa, Henna

doi:10.3389/fneur.2022.793937

Cited by 5 publications

(10 citation statements)

References 38 publications

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“…(G) NFL measurement by Simoa from serum of control individuals and PT. Each dot indicates an individual sample [control values are the same as in ( Järvilehto et al, 2021 )]. Nd = not detectable.…”

Section: Resultsmentioning

confidence: 99%

Neurofilament Light Regulates Axon Caliber, Synaptic Activity, and Organelle Trafficking in Cultured Human Motor Neurons

Sainio

Rasila

Molchanova

et al. 2022

Front. Cell Dev. Biol.

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Neurofilament light (NFL) is one of the proteins forming multimeric neuron-specific intermediate filaments, neurofilaments, which fill the axonal cytoplasm, establish caliber growth, and provide structural support. Dominant missense mutations and recessive nonsense mutations in the neurofilament light gene (NEFL) are among the causes of Charcot–Marie–Tooth (CMT) neuropathy, which affects the peripheral nerves with the longest axons. We previously demonstrated that a neuropathy-causing homozygous nonsense mutation in NEFL led to the absence of NFL in patient-specific neurons. To understand the disease-causing mechanisms, we investigate here the functional effects of NFL loss in human motor neurons differentiated from induced pluripotent stem cells (iPSC). We used genome editing to generate NEFL knockouts and compared them to patient-specific nonsense mutants and isogenic controls. iPSC lacking NFL differentiated efficiently into motor neurons with normal axon growth and regrowth after mechanical axotomy and contained neurofilaments. Electrophysiological analysis revealed that motor neurons without NFL fired spontaneous and evoked action potentials with similar characteristics as controls. However, we found that, in the absence of NFL, human motor neurons 1) had reduced axonal caliber, 2) the amplitude of miniature excitatory postsynaptic currents (mEPSC) was decreased, 3) neurofilament heavy (NFH) levels were reduced and no compensatory increases in other filament subunits were observed, and 4) the movement of mitochondria and to a lesser extent lysosomes was increased. Our findings elaborate the functional roles of NFL in human motor neurons. NFL is not only a structural protein forming neurofilaments and filling the axonal cytoplasm, but our study supports the role of NFL in the regulation of synaptic transmission and organelle trafficking. To rescue the NFL deficiency in the patient-specific nonsense mutant motor neurons, we used three drugs, amlexanox, ataluren (PTC-124), and gentamicin to induce translational read-through or inhibit nonsense-mediated decay. However, the drugs failed to increase the amount of NFL protein to detectable levels and were toxic to iPSC-derived motor neurons.

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Section: Resultsmentioning

confidence: 99%

Neurofilament Light Regulates Axon Caliber, Synaptic Activity, and Organelle Trafficking in Cultured Human Motor Neurons

Sainio

Rasila

Molchanova

et al. 2022

Front. Cell Dev. Biol.

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“…Plasma GDF15 was measured with ELISA as described previously [ 33 ]. Plasma NFL and glial fibrillary acidic protein (GFAP) levels were quantified with the Quanterix single molecule array (Simoa, Billerica, MA, USA) HD-X analyzer using the Neuro 2-Plex B kit (ref# 103,520) according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Rare PMP22 variants in mild to severe neuropathy uncorrelated to plasma GDF15 or neurofilament light

Palu,

Järvilehto,

Pennonen

et al. 2023

Neurogenetics

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Charcot-Marie-Tooth disease (CMT) is a heterogeneous set of hereditary neuropathies whose genetic causes are not fully understood. Here, we characterize three previously unknown variants in PMP22 and assess their effect on the recently described potential CMT biomarkers’ growth differentiation factor 15 (GDF15) and neurofilament light (NFL): first, a heterozygous PMP22 c.178G > A (p.Glu60Lys) in one mother-son pair with adult-onset mild axonal neuropathy. The variant led to abnormal splicing, confirmed in fibroblasts by reverse transcription PCR. Second, a de novo PMP22 c.35A > C (p.His12Pro), and third, a heterozygous 3.2 kb deletion predicting loss of exon 4. The latter two had severe CMT and ultrasonography showing strong nerve enlargement similar to a previous case of exon 4 loss due to a larger deletion. We further studied patients with PMP22 duplication (CMT1A) finding slightly elevated plasma NFL, as measured by the single molecule array immunoassay (SIMOA). In addition, plasma GDF15, as measured by ELISA, correlated with symptom severity for CMT1A. However, in the severely affected individuals with PMP22 exon 4 deletion or p.His12Pro, these biomarkers were within the range of variability of CMT1A and controls, although they had more pronounced nerve hypertrophy. This study adds p.His12Pro and confirms PMP22 exon 4 deletion as causes of severe CMT, whereas the previously unknown splice variant p.Glu60Lys leads to mild axonal neuropathy. Our results suggest that GDF15 and NFL do not distinguish CMT1A from advanced hypertrophic neuropathy caused by rare PMP22 variants.

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“…Efforts to develop and characterize mouse models of SMAJ are ongoing, but no publications are available at the time of writing this Review. In addition, serum samples of SMAJ patients have been investigated to identify biomarkers for monitoring the effects of treatment trials in the future ( Järvilehto et al, 2022 ).…”

Section: The Fdhmentioning

confidence: 99%

The Finnish genetic heritage in 2022 – from diagnosis to translational research

Uusimaa

Kettunen

Varilo

et al. 2022

Disease Models &Amp; Mechanisms

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Isolated populations have been valuable for the discovery of rare monogenic diseases and their causative genetic variants. Finnish disease heritage (FDH) is an example of a group of hereditary monogenic disorders caused by single major, usually autosomal-recessive, variants enriched in the population due to several past genetic drift events. Interestingly, distinct subpopulations have remained in Finland and have maintained their unique genetic repertoire. Thus, FDH diseases have persisted, facilitating vigorous research on the underlying molecular mechanisms and development of treatment options. This Review summarizes the current status of FDH, including the most recently discovered FDH disorders, and introduces a set of other recently identified diseases that share common features with the traditional FDH diseases. The Review also discusses a new era for population-based studies, which combine various forms of big data to identify novel genotype–phenotype associations behind more complex conditions, as exemplified here by the FinnGen project. In addition to the pathogenic variants with an unequivocal causative role in the disease phenotype, several risk alleles that correlate with certain phenotypic features have been identified among the Finns, further emphasizing the broad value of studying genetically isolated populations.

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Serum Creatine, Not Neurofilament Light, Is Elevated in CHCHD10-Linked Spinal Muscular Atrophy

Cited by 5 publications

References 38 publications

Neurofilament Light Regulates Axon Caliber, Synaptic Activity, and Organelle Trafficking in Cultured Human Motor Neurons

Neurofilament Light Regulates Axon Caliber, Synaptic Activity, and Organelle Trafficking in Cultured Human Motor Neurons

Rare PMP22 variants in mild to severe neuropathy uncorrelated to plasma GDF15 or neurofilament light

The Finnish genetic heritage in 2022 – from diagnosis to translational research

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