scholarly journals Dystrophin Dp71 and the Neuropathophysiology of Duchenne Muscular Dystrophy

2019 ◽  
Vol 57 (3) ◽  
pp. 1748-1767 ◽  
Author(s):  
Michael Naidoo ◽  
Karen Anthony
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Protein Complexes ◽  
Neuropsychiatric Symptoms ◽  
Cellular Tissue ◽  
Protein Product ◽  
The Body ◽  
Brain Targeting ◽  
Cellular Functions ◽  
The Brain

AbstractDuchenne muscular dystrophy (DMD) is caused by frameshift mutations in the DMD gene that prevent the body-wide translation of its protein product, dystrophin. Besides a severe muscle phenotype, cognitive impairment and neuropsychiatric symptoms are prevalent. Dystrophin protein 71 (Dp71) is the major DMD gene product expressed in the brain and mutations affecting its expression are associated with the DMD neuropsychiatric syndrome. As with dystrophin in muscle, Dp71 localises to dystrophin-associated protein complexes in the brain. However, unlike in skeletal muscle; in the brain, Dp71 is alternatively spliced to produce many isoforms with differential subcellular localisations and diverse cellular functions. These include neuronal differentiation, adhesion, cell division and excitatory synapse organisation as well as nuclear functions such as nuclear scaffolding and DNA repair. In this review, we first describe brain involvement in DMD and the abnormalities observed in the DMD brain. We then review the gene expression, RNA processing and functions of Dp71. We review genotype-phenotype correlations and discuss emerging cellular/tissue evidence for the involvement of Dp71 in the neuropathophysiology of DMD. The literature suggests changes observed in the DMD brain are neurodevelopmental in origin and that their risk and severity is associated with a cumulative loss of distal DMD gene products such as Dp71. The high risk of neuropsychiatric syndromes in Duchenne patients warrants early intervention to achieve the best possible quality of life. Unravelling the function and pathophysiological significance of dystrophin in the brain has become a high research priority to inform the development of brain-targeting treatments for Duchenne.

scholarly journals Different Dystrophin-like Complexes Are Expressed in Neurons and Glia

1999 ◽  
Vol 147 (3) ◽  
pp. 645-658 ◽  
Author(s):  
Derek J. Blake ◽  
Richard Hawkes ◽  
Matthew A. Benson ◽  
Phillip W. Beesley
Keyword(s):  
Cognitive Impairment ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Disease ◽  
Primary Sequence ◽  
Specific Complex ◽  
Associated Proteins ◽  
Membrane Spanning ◽  
The Brain ◽  
Similar Complex

Duchenne muscular dystrophy is a fatal muscle disease that is often associated with cognitive impairment. Accordingly, dystrophin is found at the muscle sarcolemma and at postsynaptic sites in neurons. In muscle, dystrophin forms part of a membrane-spanning complex, the dystrophin-associated protein complex (DPC). Whereas the composition of the DPC in muscle is well documented, the existence of a similar complex in brain remains largely unknown. To determine the composition of DPC-like complexes in brain, we have examined the molecular associations and distribution of the dystrobrevins, a widely expressed family of dystrophin-associated proteins, some of which are components of the muscle DPC. β-Dystrobrevin is found in neurons and is highly enriched in postsynaptic densities (PSDs). Furthermore, β-dystrobrevin forms a specific complex with dystrophin and syntrophin. By contrast, α-dystrobrevin-1 is found in perivascular astrocytes and Bergmann glia, and is not PSD-enriched. α-Dystrobrevin-1 is associated with Dp71, utrophin, and syntrophin. In the brains of mice that lack dystrophin and Dp71, the dystrobrevin–syntrophin complexes are still formed, whereas in dystrophin-deficient muscle, the assembly of the DPC is disrupted. Thus, despite the similarity in primary sequence, α- and β-dystrobrevin are differentially distributed in the brain where they form separate DPC-like complexes.

The history of muscular dystrophy: a unique story

2013 ◽  
Author(s):  
Alan E. H. Emery ◽  
Marcia L. H. Emery
Keyword(s):  
Gene Therapy ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Effective Treatment ◽  
Genetic Disorder ◽  
Protein Product ◽  
Responsible Gene ◽  
History Of ◽  
Common Genetic Disorder

Chapter 1 discusses the history of Duchenne muscular dystrophy, a serious condition and the second most common genetic disorder in many countries. Its cause was unknown until relatively recently and there has been no effective treatment. However, the responsible gene and its protein product have now been identified and gene therapy is under serious consideration.

Regulation and metabolic functions of mTORC1 and mTORC2

2021 ◽  
Author(s):  
Angelia Szwed ◽  
Eugene Kim ◽  
Estela Jacinto
Keyword(s):  
Protein Complexes ◽  
Cellular Tissue ◽  
Metabolic Reprogramming ◽  
Cellular Functions ◽  
Environmental Signals ◽  
Metabolic Functions ◽  
Cancer Models ◽  
Intracellular Metabolism ◽  
Uptake Of Nutrients

Cells metabolize nutrients for biosynthetic and bioenergetic needs to fuel growth and proliferation. The uptake of nutrients from the environment and their intracellular metabolism is a highly controlled process that involves crosstalk between growth signaling and metabolic pathways. Despite constant fluctuations in nutrient availability and environmental signals, normal cells restore metabolic homeostasis to maintain cellular functions and prevent disease. A central signaling molecule that integrates growth with metabolism is the mechanistic target of rapamycin (mTOR). mTOR is a protein kinase that responds to levels of nutrients and growth signals. mTOR forms two protein complexes, mTORC1, which is sensitive to rapamycin and mTORC2, which is not directly inhibited by this drug. Rapamycin has facilitated the discovery of the various functions of mTORC1 in metabolism. Genetic models that disrupt either mTORC1 or mTORC2 have expanded our knowledge on their cellular, tissue as well as systemic functions in metabolism. Nevertheless, our knowledge on the regulation and functions of mTORC2, particularly in metabolism, has lagged behind. Since mTOR is an important target for cancer, aging and other metabolism-related pathologies, understanding the distinct and overlapping regulation and functions of the two mTOR complexes is vital for the development of more effective therapeutic strategies. This review will discuss the key discoveries and recent findings on the regulation and metabolic functions of the mTOR complexes. We highlight findings from cancer models, but also discuss other examples of the mTOR-mediated metabolic reprogramming occurring in stem and immune cells, type 2 diabetes/obesity, neurodegenerative disorders and aging.

scholarly journals Detection of a specific isoform of alpha-actinin with antisera directed against dystrophin.

1989 ◽  
Vol 108 (2) ◽  
pp. 503-510 ◽  
Author(s):  
E P Hoffman ◽  
S C Watkins ◽  
H S Slayter ◽  
L M Kunkel
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Extensor Digitorum Longus ◽  
Protein Product ◽  
Related Protein ◽  
Sequence Homologies ◽  
Fast Twitch ◽  
Restricted Pattern ◽  
Related Proteins

We have characterized a protein immunologically related to dystrophin, the protein product of the Duchenne muscular dystrophy gene. We identify this related protein as a fast-twitch glycolytic isoform (mouse extensor digitorum longus-specific) of myofibrillar alpha-actinin. This specific isoform of alpha-actinin exhibits a more restricted pattern of expression in skeletal muscle than fast-twitch-specific isoforms of both myosin and Ca2+-ATPase. Our results provide evidence that dystrophin and myofibrillar alpha-actinin are related proteins, reinforcing the previous data concerning the sequence homologies noted between nonmuscle cytoskeletal alpha-actinin and dystrophin. In addition, we describe the first antisera directed against a specific myofibrillar skeletal muscle isoform of alpha-actinin.

scholarly journals A novel product of the Duchenne muscular dystrophy gene which greatly differs from the known isoforms in its structure and tissue distribution

1990 ◽  
Vol 272 (2) ◽  
pp. 557-560 ◽  
Author(s):  
S Bar ◽  
E Barnea ◽  
Z Levy ◽  
S Neuman ◽  
D Yaffe ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Untranslated Region ◽  
Actin Binding ◽  
Duchenne Muscular Dystrophy Gene ◽  
Novel Transcript ◽  
Muscle Tissues ◽  
Actin Binding Domain ◽  
The Brain ◽  
Lung And Kidney

A novel transcript of the Duchenne muscular dystrophy gene has been identified. This 6.5 kb mRNA contains sequences from the 3′ untranslated region of dystrophin mRNA and from the regions coding for the C-terminal and the cysteine-rich domains. However, probes for the regions encoding the spectrin-like repeats and the actin-binding domain, as well as probes for the first exons of the muscle- and brain-type dystrophin mRNA, did not hybridize with this new mRNA. Significant amounts of the 6.5 kb mRNA were found in a variety of non-muscle tissues, such as liver, testis, lung and kidney, but not in skeletal muscle. The abundance of this mRNA in the brain is at least as high as that of the previously described 14 kb brain-type dystrophin mRNA.

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