Neuromuscular junction as an entity of nerve-muscle communication

One of the crucial systems severely affected in several neuromuscular diseases is the loss of effective connection between muscle and nerve, leading to a pathological non-communication between the two tissues. The neuromuscular junction (NMJ) represents the critical region at the level of which muscle and nerve communicate. Defects in signal transmission between terminal nerve endings and muscle membrane is a common feature of several physio-pathologic conditions including aging and Amyotrophic Lateral Sclerosis (ALS). Nevertheless, controversy exists on whether pathological events beginning at the NMJ precede or follow loss of motor units. In this review, the role of NMJ in the physio-pathologic interplay between muscle and nerve is discussed

A de novo variant in the bovine ADAMTSL4 gene in an Original Braunvieh calf with congenital cataract

Inherited forms of cataract are a heterogeneous group of eye disorders known in livestock species. Clinicopathological analysis of a single case of impaired vision in a newborn Original Braunvieh calf revealed nuclear cataract. Whole-genome sequencing of the parent-offspring trio revealed a de novo mutation of ADAMTSL4 in this case. The heterozygous p.Arg776His missense variant affects a conserved residue of the ADAMTSL4 gene that encodes a secreted glycoprotein expressed in the lens throughout embryonic development. In humans, ADAMTSL4 genetic variants cause recessively inherited forms of subluxation of the lens. Given that ADAMTSL4 is a functional candidate gene for inherited disorders of the lens, we suggest that heterozygosity for the identified missense variant may have caused the congenital cataract in the affected calf. Cattle populations should be monitored for unexplained cataract cases, with subsequent DNA sequencing a hypothesized pathogenic effect of heterozygous ADAMTSL4 variants could be confirmed

A de novo variant in the bovine ADAMTSL4 gene in an Original Braunvieh calf with congenital cataract

Inherited forms of cataract are a heterogeneous group of eye disorders known in livestock species. Clinicopathological analysis of a single case of impaired vision in a newborn Original Braunvieh calf revealed nuclear cataract. Whole-genome sequencing of the parent-offspring trio revealed a de novo mutation of ADAMTSL4 in this case. The heterozygous p.Arg776His missense variant affects a conserved residue of the ADAMTSL4 gene that encodes a secreted glycoprotein expressed in the lens throughout embryonic development. In humans, ADAMTSL4 genetic variants cause recessively inherited forms of subluxation of the lens. Given that ADAMTSL4 is a functional candidate gene for inherited disorders of the lens, we suggest that heterozygosity for the identified missense variant may have caused the congenital cataract in the affected calf. Cattle populations should be monitored for unexplained cataract cases, with subsequent DNA sequencing a hypothesized pathogenic effect of heterozygous ADAMTSL4 variants could be confirmed

Circulating myomiRs in Muscle Denervation: From Surgical to ALS Pathological Condition

ALS is a fatal neurodegenerative disease that is associated with muscle atrophy, motoneuron degeneration and denervation. Different mechanisms have been proposed to explain the pathogenesis of the disease; in this context, microRNAs have been described as biomarkers and potential pathogenetic factors for ALS. MyomiRs are microRNAs produced by skeletal muscle, and they play an important role in tissue homeostasis; moreover, they can be released in blood circulation in pathological conditions, including ALS. However, the functional role of myomiRs in muscle denervation has not yet been fully clarified. In this study, we analyze the levels of two myomiRs, namely miR-206 and miR-133a, in skeletal muscle and blood samples of denervated mice, and we demonstrate that surgical denervation reduces the expression of both miR-206 and miR-133a, while miR-206 but not miR-133a is upregulated during the re-innervation process. Furthermore, we quantify the levels of miR-206 and miR-133a in serum samples of two ALS mouse models, characterized by different disease velocities, and we demonstrate a different modulation of circulating myomiRs during ALS disease, according to the velocity of disease progression. Moreover, taking into account surgical and pathological denervation, we describe a different response to increasing amounts of circulating miR-206, suggesting a hormetic effect of miR-206 in relation to changes in neuromuscular communication

Fenretinide beneficial effects on amyotrophic lateral sclerosis-associated SOD1G93A mutant protein toxicity: in vitro and In vivo evidences

Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease for which effective treatment options are still lacking. ALS occurs in sporadic and familial forms which are clinically indistinguishable; about 20% of familial ALS cases are linked to mutations of the superoxide dismutase 1 (SOD1) gene. Fenretinide (FEN), a cancer chemopreventive and antiproliferative agent currently used in several clinical trials, is a multi-target drug which also exhibits redox regulation activities. We analyzed the effects of FEN on mutant SOD1 (mSOD1) toxicity in motoneuronal (NSC34) and a muscle (C2C12) cell lines and evaluated the impacts of chronic administration of a new nanomicellar fenretinide formulation (NanoMFen) on ALS disease progression in the SOD1G93A mouse model. The results showed that FEN significantly prevents the toxicity of mSOD1 expression in NSC34 motor neuron; furthermore, FEN is able to partially overcome the toxic effect of mSOD1 on the myogenic program of C2C12 muscle cells. Administration of NanoMFen ameliorates the disease progression and increases median survival of mSOD1G93A ALS mice, even when given after disease onset; beneficial effects in ALS mice, however, is restricted to female sex. Our data support the therapeutic potential of FEN against ALS-associated SOD1G93A mutant protein toxicity and promote further studies to elucidate specific cellular targets of the drug in ALS. Furthermore, the sex-related efficacy of NanoMFen in mSOD1G93A ALS mice strengthens the importance, in the perspective of a precision medicine approach, of gender pharmacology in ALS research

Individuals with &ITFANCM&IT biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility

Purpose: Monoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.& para;& para;Methods: Breast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.& para;& para;Results: Five cases homozygous for FANCM loss-of-function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. Phenotype severity might correlate with mutation position in the gene.& para;& para;Conclusion: Our data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features