Organoid culture promotes dedifferentiation of mouse myoblasts into stem cells capable of complete muscle regeneration.

Experimental cell therapies for skeletal muscle conditions have shown little success, primarily because they use committed myogenic progenitors rather than true muscle stem cells, known as satellite cells. Here we present a method to generate in vitro-derived satellite cells (idSCs) from skeletal muscle tissue. When transplanted in small numbers into mouse muscle, mouse idSCs fuse into myofibers, repopulate the satellite cell niche, self-renew, support multiple rounds of muscle regeneration and improve force production on par with freshly isolated satellite cells in damaged skeletal muscle.

A high-throughput genome-wide RNAi screen identifies modifiers of survival motor neuron protein.

Spinal muscular atrophy (SMA) is a debilitating neurological disorder marked by degeneration of spinal motor neurons and muscle atrophy. SMA results from mutations in survival motor neuron 1 (SMN1), leading to deficiency of survival motor neuron (SMN) protein. Current therapies increase SMN protein and improve patient survival but have variable improvements in motor function, making it necessary to identify complementary strategies to further improve disease outcomes.

Spinal Muscular Atrophy: Huge Steps.

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Toward Precision Medicine for Neurological and Neuropsychiatric Disorders.

The genetic complexity, clinical variability, and inaccessibility of affected tissue in neurodegenerative and neuropsychiatric disorders have largely prevented the development of effective disease-modifying therapeutics. A precision medicine approach that integrates genomics, deep clinical phenotyping, and patient stem cell models may facilitate identification of underlying biological drivers and targeted drug development.

Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes.

Spinal muscular atrophy (SMA), a degenerative motor neuron (MN) disease, caused by loss of functional survival of motor neuron (SMN) protein due to SMN1 gene mutations, is a leading cause of infant mortality. Increasing SMN levels ameliorates the disease phenotype and is unanimously accepted as a therapeutic approach for patients with SMA. The ubiquitin/proteasome system is known to regulate SMN protein levels; however, whether autophagy controls SMN levels remains poorly explored.

The DcpS inhibitor RG3039 improves motor function in SMA mice.

Spinal muscular atrophy (SMA) is caused by mutations of the survival motor neuron 1 (SMN1) gene, retention of the survival motor neuron 2 (SMN2) gene and insufficient expression of full-length survival motor neuron (SMN) protein. Quinazolines increase SMN2 promoter activity and inhibit the ribonucleic acid scavenger enzyme DcpS. The quinazoline derivative RG3039 has advanced to early phase clinical trials.

Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model.

Evaluation of B-type natriuretic peptide for validation of a heart failure register in primary care.

Background: Diagnosing heart failure and left ventricular systolic dysfunction is difficult on clinical grounds alone. We sought to determine the accuracy of a heart failure register in a single primary care practice, and to examine the usefulness of b-type (or brain) natriuretic peptide (BNP) assay for this purpose.

Methods: A register validation audit in a single general practice in the UK was carried out.

A family with a tau P301L mutation presenting with parkinsonism.

We report a sib-pair with a tau P301L mutation. Unlike most previous cases with this mutation, parkinsonism, rather than dementing features were the predominant and presenting feature. We have also observed that the P301L mutation has occurred on the H1 tau haplotype background.