LAMA2 Neuropathies: Human Findings and Pathomechanisms From Mouse Models

Previtali, Stefano C.; Zambon, Alberto A.

doi:10.3389/fnmol.2020.00060

Cited by 23 publications

(26 citation statements)

References 113 publications

(170 reference statements)

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“…Mild-to-moderate cognitive disability is reported in a small proportion of LAMA2-RD patients (Messina et al, 2010 ) and one series was associated with additional structural occipital cortex abnormalities (Mercuri et al, 1999 ). Mild, sensorimotor demyelinating neuropathy is commonly observed, but its contribution to muscle weakness is considered to be minimal in the human, while it plays a substantial role in mouse models of lama2 deficiency (Shorer et al, 1995 ; Previtali and Zambon, 2020 ).…”

Section: Lama2-rd: Clinical Aspectsmentioning

confidence: 99%

LAMA2-Related Dystrophies: Clinical Phenotypes, Disease Biomarkers, and Clinical Trial Readiness

Sárközy

Foley

Zambon

et al. 2020

Front. Mol. Neurosci.

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LAMA2-RD: Clinical Phenotypes and Biomarkers a five-year prospective natural history and comparative outcome measures study in patients with LAMA2-RD, have helped to better delineate the natural history and identify viable outcome measures. Plans for further clinical trials for LAMA2-RDs are presently in progress, highlighting the necessity of identifying adequate, disease-relevant biomarkers, capable of reflecting potential therapeutic changes, in addition to refining the clinical outcome measures and time-to-event trajectory analysis of affected patients.

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Section: Lama2-rd: Clinical Aspectsmentioning

confidence: 99%

LAMA2-Related Dystrophies: Clinical Phenotypes, Disease Biomarkers, and Clinical Trial Readiness

Sárközy

Foley

Zambon

et al. 2020

Front. Mol. Neurosci.

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“…Schwann cells transform from the myelinating phenotype to a reparative phenotype via EMT mechanisms[29,30]. Our results show that proteins expressed by Schwann cells such as PRX and LAMA2[37,38] were downregulated after injury. We showed the upregulation of proteins in the EMT GO pathway, including SFRP2 (Fig 6).…”

Section: Discussionmentioning

confidence: 90%

Transection injury differentially alters the proteome of the human sural nerve

Chau

Quintero

Blalock

et al. 2021

Preprint

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Regeneration after severe peripheral nerve injury is often poor. Knowledge of human nerve regeneration and the growth microenvironment is greatly lacking. We aimed to identify the regenerative proteins in human peripheral nerve by comparing the proteome before and after a transection injury. In a unique study design, we collected from the same participants, samples from naïve and degenerating sural nerve. Naïve and degenerating (two weeks after injury) samples were analyzed using mass spectrometry and immunoassays. Using a correlation matrix, we found significantly altered levels following the nerve injury. Mass spectrometry revealed that post-injury samples had 672 proteins significantly upregulated and 661 significantly downregulated compared to naïve samples (q < 0.05, |FC| > 2). We used Gene Ontology pathways to highlight groups of proteins that were significantly upregulated or downregulated with injury-induced degeneration and regeneration. Significant protein changes in key pathways were identified including growth factor levels, Schwann cell de-differentiation, myelination downregulation, epithelial-mesenchymal transition, and axonal regeneration pathways. Having proteome signatures of human peripheral nerves of both the uninjured and the degenerating/regenerating state may serve as biomarkers to aid in the future development of repair strategies and in monitoring neural tissue regeneration.

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“…14 CDC42 is involved in several processes in Schwann cells, including endocytosis for regulation of protein and lipids, vesicular transport, proper matching of axon-Schwann cell units, and rearrangement of the cytoskeleton in radial sorting. 5,10,13,25,30 FGD4 is also required for efficient endocytosis. 14 In addition, frabin has FYVE and PH domains that suggest it could interact with myotubularin-related proteins (MTMR2) which are required for membrane trafficking.…”

Section: Discussionmentioning

confidence: 99%

Pathology of the peripheral neuropathy Charcot-Marie-Tooth disease type 4H in Holstein Friesian cattle with a splice site mutation in FGD4

et al. 2022

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Charcot-Marie-Tooth disease (CMT) is a hereditary sensory and motor peripheral neuropathy that is one of the most common inherited neurological diseases of humans and may be caused by mutations in a number of different genes. The subtype Charcot-Marie-Tooth disease type 4H (CMT4H) is caused by homozygous mutations in the FGD4 (FYVE, RhoGEF, and PH domain-containing 4) gene. A previous genome-wide association study involving 130,783 dairy cows found 6 novel variants, one of which was a homozygous splice site mutation in the FGD4 gene. Descendants of carriers were genotyped to identify 9 homozygous Holstein Friesian calves that were raised to maturity, of which 5 were euthanized and sampled for histopathology and electron microscopy at 2 and 2.5 years of age. Three control Holstein Friesian animals were raised with the calves and euthanized at the same time points. No macroscopic lesions consistent with CMT4H were seen at necropsy. Microscopically, peripheral nerves were hypercellular due to hyperplasia of S100-positive Schwann cells, and there was onion bulb formation, axonal degeneration with demyelination, and increased thickness of the endoneurium. On electron microscopy, decreased axonal density, onion bulb formations, myelin outfoldings, and increased numbers of mitochondria were present. These changes are consistent with those described in mouse models and humans with CMT4H, making these cattle a potential large animal model for CMT.

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LAMA2 Neuropathies: Human Findings and Pathomechanisms From Mouse Models

Cited by 23 publications

References 113 publications

LAMA2-Related Dystrophies: Clinical Phenotypes, Disease Biomarkers, and Clinical Trial Readiness

LAMA2-Related Dystrophies: Clinical Phenotypes, Disease Biomarkers, and Clinical Trial Readiness

Transection injury differentially alters the proteome of the human sural nerve

Pathology of the peripheral neuropathy Charcot-Marie-Tooth disease type 4H in Holstein Friesian cattle with a splice site mutation in FGD4

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