Evaluation of peripherin in biofluids of patients with motor neuron diseases

Sabbatini, Daniele; Raggi, Flavia; Ruggero, Susanna; Seguso, Mara; Mandrioli, Jessica; Cagnin, Annachiara; Briani, Chiara; Toffanin, Elisabetta; Gizzi, Matteo; Fortuna, Andrea; Bello, Luca; Pegoraro, Elena; Musso, Giulia; Sorarù, Gianni

doi:10.1002/acn3.51419

Cited by 12 publications

(8 citation statements)

References 25 publications

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“…Different subunits might reflect different neurodegenerative processes. In addition to commonly used NfL and pNfH, some studies also found potential values of other Nf subunits, i.e., NfM ( Hu et al, 2002 ; Haggmark et al, 2014 ; Martinez-Morillo et al, 2014 ; Zucchi et al, 2018 ; Remnestal et al, 2020 ), INA ( Martinez-Morillo et al, 2014 ) and PRPH ( Finderlater, 2010 ; Liang et al, 2019 ; Sabbatini et al, 2021 ) as biomarkers in CSF or serum in neurological diseases or injuries.…”

Section: Properties Of Neurofilaments Relevant To Their Use As Biomarkersmentioning

confidence: 99%

“…Moreover, PRPH is also sensitive to diffuse axonal injury ( Liang et al, 2019 ) and its aggregate-inducing isoform Per 28 is upregulated in ALS and is associated with disease pathology ( Xiao et al, 2008 ). A recent report suggests high serum levels of PRPH might be a general biomarker of axon disorders of lower motor neurons ( Sabbatini et al, 2021 ). Future studies should therefore aim to develop assays of appropriate specificity for each of the NfP subunits or degradation fragments to explore the complementary information they may contribute to NfP pathobiology and use as biomarkers.…”

Section: Current Research Gaps and Potential Development Of Neurofilaments As Biomarkersmentioning

confidence: 99%

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Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

2021

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Biomarkers of neurodegeneration and neuronal injury have the potential to improve diagnostic accuracy, disease monitoring, prognosis, and measure treatment efficacy. Neurofilament proteins (NfPs) are well suited as biomarkers in these contexts because they are major neuron-specific components that maintain structural integrity and are sensitive to neurodegeneration and neuronal injury across a wide range of neurologic diseases. Low levels of NfPs are constantly released from neurons into the extracellular space and ultimately reach the cerebrospinal fluid (CSF) and blood under physiological conditions throughout normal brain development, maturation, and aging. NfP levels in CSF and blood rise above normal in response to neuronal injury and neurodegeneration independently of cause. NfPs in CSF measured by lumbar puncture are about 40-fold more concentrated than in blood in healthy individuals. New ultra-sensitive methods now allow minimally invasive measurement of these low levels of NfPs in serum or plasma to track disease onset and progression in neurological disorders or nervous system injury and assess responses to therapeutic interventions. Any of the five Nf subunits – neurofilament light chain (NfL), neurofilament medium chain (NfM), neurofilament heavy chain (NfH), alpha-internexin (INA) and peripherin (PRPH) may be altered in a given neuropathological condition. In familial and sporadic Alzheimer’s disease (AD), plasma NfL levels may rise as early as 22 years before clinical onset in familial AD and 10 years before sporadic AD. The major determinants of elevated levels of NfPs and degradation fragments in CSF and blood are the magnitude of damaged or degenerating axons of fiber tracks, the affected axon caliber sizes and the rate of release of NfP and fragments at different stages of a given neurological disease or condition directly or indirectly affecting central nervous system (CNS) and/or peripheral nervous system (PNS). NfPs are rapidly emerging as transformative blood biomarkers in neurology providing novel insights into a wide range of neurological diseases and advancing clinical trials. Here we summarize the current understanding of intracellular NfP physiology, pathophysiology and extracellular kinetics of NfPs in biofluids and review the value and limitations of NfPs and degradation fragments as biomarkers of neurodegeneration and neuronal injury.

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Section: Properties Of Neurofilaments Relevant To Their Use As Biomarkersmentioning

confidence: 99%

Section: Current Research Gaps and Potential Development Of Neurofilaments As Biomarkersmentioning

confidence: 99%

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

2021

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“…Prph , a neuronal intermediate filament protein implicated in ALS, showed the largest fold-changes (<−0.5 log 2 -fold change) in our transcriptomic analysis and was selectively downregulated in specific motor pools in Isl2 mutant mice. In addition, earlier extinction of Prph in developing motor neurons correlated with progressive degeneration of spinal motor neurons and NMJs, which indicated that the defects observed in Isl2 mutant mice are relevant to early-onset progressive motor neuron disorders such as SMA and ALS (Amin et al, 2015; Amin et al, 2021; Beaulieu & Julien, 2003; Chen, Sayana, Zhang, & Le, 2013; Gros-Louis et al, 2004; Sabbatini et al, 2021). Similarly, C-type lectin chondrolectin ( Chodl ) is a known marker for fast MNs and is involved in cell survival and neurite outgrowth in MNs (Enjin et al, 2010; Sleigh et al, 2014).…”

Section: Discussionmentioning

confidence: 98%

Transcriptional control of motor pool formation and motor circuit connectivity by the LIM-HD protein Isl2

Lee

Yeo

Kim

et al. 2022

Preprint

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The fidelity of motor control requires the precise positional arrangement of motor pools and the establishment of synaptic connections between these pools. In the developing spinal cord, motor nerves project to specific target muscles and receive proprioceptive input from the muscles via the sensorimotor circuit. LIM-homeodomain transcription factors are known to successively restrict specific motor neuronal fates during neural development; however, it remains unclear to what extent they contribute to limb-based motor pools and locomotor circuits. Here, we showed in mice that deletion of Isl2 resulted in scattered motor pools, primarily in the median motor column and lateral LMC (LMCl) populations, and lacked Pea3 expression in the hindlimb motor pools, accompanied by reduced terminal axon branching and disorganized neuromuscular junctions. Transcriptomic analysis of Isl2-deficient spinal cords revealed that a variety of genes involved in motor neuron differentiation, axon development, and synapse organization were downregulated in hindlimb motor pools. Moreover, the loss of Isl2 impaired sensorimotor connectivity and hindlimb locomotion. Together, our studies indicate that Isl2 plays a critical role in organizing motor pool position and sensorimotor circuits in hindlimb motor pools.

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“…Finally, spheroid proteins are among the most promising candidate biomarkers for ALS, as exemplified by pNF-H ( 53 – 56 ) and peripherin ( 57 ). As for the application of CRMPs, the pCRMP2:CRMP2 ratio in lymphocytes was recently reported to be a useful biomarker for schizophrenia ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylated CRMP1, axon guidance protein, is a component of spheroids and is involved in axonal pathology in amyotrophic lateral sclerosis

et al. 2022

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In amyotrophic lateral sclerosis (ALS), neurodegeneration is characterized by distal axonopathy that begins at the distal axons, including the neuromuscular junctions, and progresses proximally in a “dying back” manner prior to the degeneration of cell bodies. However, the molecular mechanism for distal axonopathy in ALS has not been fully addressed. Semaphorin 3A (Sema3A), a repulsive axon guidance molecule that phosphorylates collapsin response mediator proteins (CRMPs), is known to be highly expressed in Schwann cells near distal axons in a mouse model of ALS. To clarify the involvement of Sema3A–CRMP signaling in the axonal pathogenesis of ALS, we investigated the expression of phosphorylated CRMP1 (pCRMP1) in the spinal cords of 35 patients with sporadic ALS and seven disease controls. In ALS patients, we found that pCRMP1 accumulated in the proximal axons and co-localized with phosphorylated neurofilaments (pNFs), which are a major protein constituent of spheroids. Interestingly, the pCRMP1:pNF ratio of the fluorescence signal in spheroid immunostaining was inversely correlated with disease duration in 18 evaluable ALS patients, indicating that the accumulation of pCRMP1 may precede that of pNFs in spheroids or promote ALS progression. In addition, overexpression of a phospho-mimicking CRMP1 mutant inhibited axonal outgrowth in Neuro2A cells. Taken together, these results indicate that pCRMP1 may be involved in the pathogenesis of axonopathy in ALS, leading to spheroid formation through the proximal progression of axonopathy.

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Evaluation of peripherin in biofluids of patients with motor neuron diseases

Cited by 12 publications

References 25 publications

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

Transcriptional control of motor pool formation and motor circuit connectivity by the LIM-HD protein Isl2

Phosphorylated CRMP1, axon guidance protein, is a component of spheroids and is involved in axonal pathology in amyotrophic lateral sclerosis

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