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International Review of Cell and... 2013Neuronal dystonin isoforms are giant cytoskeletal cross-linking proteins capable of interacting with actin and microtubule networks, protein complexes, membrane-bound... (Review)
Review
Neuronal dystonin isoforms are giant cytoskeletal cross-linking proteins capable of interacting with actin and microtubule networks, protein complexes, membrane-bound organelles and cellular membranes. In the neuromuscular system, dystonin proteins are involved in maintaining cytoarchitecture integrity and have more recently been ascribed roles in other cellular processes such as organelle structure and intracellular transport. Loss of dystonin expression in mice results in a profound sensory ataxia termed dystonia musculorum (dt), which is attributed to the degeneration of sensory nerves. This chapter provides a comprehensive overview of the dystonin gene, the structure of encoded proteins, biological functions of neuronal dystonin isoforms, and known roles of dystonin in dt pathogenesis and human disease.
Topics: Animals; Carrier Proteins; Cytoskeletal Proteins; Dystonin; Genetic Variation; Humans; Mice; Models, Neurological; Molecular Biology; Mutation; Nerve Degeneration; Nerve Tissue Proteins; Protein Isoforms; Protein Structure, Tertiary; Sensory Receptor Cells; Subcellular Fractions
PubMed: 23273860
DOI: 10.1016/B978-0-12-405210-9.00003-5 -
Biochemistry and Cell Biology =... Jun 2021The neuronal dystonin protein (DST-a) is a large cytoskeletal linker important for integrating the various components of the cytoskeleton. Recessive mutations lead to a...
The neuronal dystonin protein (DST-a) is a large cytoskeletal linker important for integrating the various components of the cytoskeleton. Recessive mutations lead to a sensory neuropathy in mice, known as dystonia musculorum (). The disease is characterized by ataxia, autonomic disturbances, and ultimately, death, which are associated with massive degeneration of the sensory neurons in the dorsal root ganglion (DRG). Recent investigation of sensory neurons revealed an accumulation of autophagosomes and a disruption in autophagic flux, which was believed to be due to insufficient availability of motor protein. Motor protein levels and the endolysosomal pathway were assessed in pre-symptomatic (postnatal day 5; P5) and symptomatic (P15) stage wild-type and DRGs. Levels of mRNA encoding molecular motors were reduced, although no significant reduction in the protein level was detected. An increase in lysosomal marker LAMP1 in medium-large size sensory neurons was observed, along with an accumulation of electron-light single-membraned vesicles in DRG tissue at the late stages of disease. These vesicles are likely to have been autolysosomes, and their presence in only late-stage sensory neurons is suggestive of a pathological defect in autophagy. Further investigation is necessary to confirm vesicle identity, and to determine the role of Dst-a in normal autophagic flux.
Topics: Animals; Autophagosomes; Autophagy; Dystonin; Endosomes; Ganglia, Spinal; Loss of Function Mutation; Lysosomes; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons
PubMed: 33347391
DOI: 10.1139/bcb-2020-0557 -
Cell Motility and the Cytoskeleton Dec 2007The dystonin/Bpag1 cytoskeletal interacting proteins play important roles in maintaining cytoarchitecture integrity in skin and in the neuromuscular system. The most...
The dystonin/Bpag1 cytoskeletal interacting proteins play important roles in maintaining cytoarchitecture integrity in skin and in the neuromuscular system. The most profound phenotype observed in the dystonin mutant dystonia musculorum (dt) mice is a severe movement disorder, attributed in large part to sensory neuron degeneration. The molecular basis for this phenotype is currently not clear, despite several studies indicating possible causes for the pathology in dt mice. Complicating the picture of what essential dystonin functions are lost in dt mice is the fact that our understanding of the very nature of what dystonin is has evolved greatly over the past decade. Elucidating the roles of dystonin most relevant to neuronal function and survival should help to shed light on some of the common mechanisms underlying neurodegeneration.
Topics: Amino Acid Sequence; Animals; Carrier Proteins; Cytoskeletal Proteins; Dystonin; Mice; Mice, Mutant Strains; Molecular Sequence Data; Muscles; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons
PubMed: 17849487
DOI: 10.1002/cm.20235 -
Anatomical Science International Jan 2024Dystonin (DST), also known as bullous pemphigoid antigen 1 (BPAG1), encodes cytoskeletal linker proteins belonging to the plakin family. The DST gene produces several... (Review)
Review
Dystonin (DST), also known as bullous pemphigoid antigen 1 (BPAG1), encodes cytoskeletal linker proteins belonging to the plakin family. The DST gene produces several isoforms, including DST-a, DST-b, and DST-e, which are expressed in neural, muscle, and cutaneous tissues, respectively. Pathogenic DST mutations cause hereditary sensory and autonomic neuropathy type 6 (HSAN-VI) and epidermolysis bullosa simplex (EBS); therefore, it is important to elucidate the roles of DST isoforms in multiple organs. Recently, we have used several Dst mutant mouse strains, in which the expression of Dst isoforms is disrupted in distinct patterns, to gain new insight into how DST functions in multiple tissues. This review provides an overview of the roles played by tissue-specific DST isoforms in neural, muscle, and cutaneous tissues.
Topics: Mice; Animals; Dystonin; Cytoskeletal Proteins; Nerve Tissue Proteins; Protein Isoforms; Muscles
PubMed: 37603210
DOI: 10.1007/s12565-023-00739-1 -
American Journal of Medical Genetics.... Apr 2022The DST gene is located on chromosome 6p and encodes for a large protein. Alternative splicing of this protein produces the neuronal (a1-a3), muscular (b1-b3), and... (Review)
Review
The DST gene is located on chromosome 6p and encodes for a large protein. Alternative splicing of this protein produces the neuronal (a1-a3), muscular (b1-b3), and epithelial (e) isoforms. Hereditary sensory and autonomic neuropathy (HSAN) type VI is a rare autosomal recessive disorder due to mutations affecting the a2 isoform. We present a case of HSAN-VI in a male neonate born to consanguineous parents. Genome sequencing revealed a novel homozygous variant (DST_c.1118C > T; p.Pro373Leu) inherited from both parents. This case further expands the phenotype and genotype of this rare syndrome.
Topics: Dystonin; Hereditary Sensory and Autonomic Neuropathies; Humans; Infant; Male; Neurons; Phenotype; Protein Isoforms
PubMed: 34897952
DOI: 10.1002/ajmg.a.62609 -
Neurological Sciences : Official... Aug 2019Dementia is one of the diabetic complications under intensive study. Alteration of synaptic adhesion protein (SAP) associates with neurological diseases, including... (Meta-Analysis)
Meta-Analysis
Dementia is one of the diabetic complications under intensive study. Alteration of synaptic adhesion protein (SAP) associates with neurological diseases, including Alzheimer's disease. However, the regulation of SAPs in the brain of diabetes mellitus remains elusive. To pinpoint the candidate SAPs underlining the mechanism of diabetic dementia, we investigated expression profiling of SAPs in both streptozotocin (STZ)-induced diabetic mice, App mice, and amyloid precursor protein intracellular domain (AICD)-induced human neural cell line from public databases. DST (Dystonin/BPAG1) was identified upregulated in both models. Our finding suggests that DST alteration may involve in the mechanism of diabetic dementia.
Topics: Alzheimer Disease; Animals; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Dystonin; Humans; Mice
PubMed: 30963337
DOI: 10.1007/s10072-019-03879-3 -
PloS One 2023The Lamc2jeb junctional epidermolysis bullosa (EB) mouse model has been used to demonstrate that significant genetic modification of EB symptoms is possible, identifying...
The Lamc2jeb junctional epidermolysis bullosa (EB) mouse model has been used to demonstrate that significant genetic modification of EB symptoms is possible, identifying as modifiers Col17a1 and six other quantitative trait loci, several with strong candidate genes including dystonin (Dst/Bpag1). Here, CRISPR/Cas9 was used to alter exon 23 in mouse skin specific isoform Dst-e (Ensembl GRCm38 transcript name Dst-213, transcript ID ENSMUST00000183302.5, protein size 2639AA) and validate a proposed arginine/glutamine difference at amino acid p1226 in B6 versus 129 mice as a modifier of EB. Frame shift deletions (FSD) in mouse Dst-e exon 23 (Dst-eFSD/FSD) were also identified that cause mice carrying wild-type Lamc2 to develop a phenotype similar to human EB simplex without dystonia musculorum. When combined, Dst-eFSD/FSD modifies Lamc2jeb/jeb (FSD+jeb) induced disease in unexpected ways implicating an altered balance between DST-e (BPAG1e) and a rarely reported rodless DST-eS (BPAG1eS) in epithelium as a possible mechanism. Further, FSD+jeb mice with pinnae removed are found to provide a test bed for studying internal epithelium EB disease and treatment without severe skin disease as a limiting factor while also revealing and accelerating significant nasopharynx symptoms present but not previously noted in Lamc2jeb/jeb mice.
Topics: Animals; Mice; Dystonia; Dystonic Disorders; Dystonin; Epidermolysis Bullosa; Epidermolysis Bullosa Simplex; Epidermolysis Bullosa, Junctional; Skin
PubMed: 37883475
DOI: 10.1371/journal.pone.0293218 -
Molecular and Cellular Neurosciences Apr 1998The mouse neurological mutant dystonia musculorum (dt) suffers from a hereditary sensory neuropathy. We have previously described the cloning and characterization of the...
The mouse neurological mutant dystonia musculorum (dt) suffers from a hereditary sensory neuropathy. We have previously described the cloning and characterization of the dt gene, which we named dystonin (Dst). We had shown that dystonin is a neural isoform of bullous pemphigoid antigen 1 (Bpag1) with an N-terminal actin-binding domain. It has been shown previously that dystonin is a cytoskeletal linker protein, forming a bridge between F-actin and intermediate filaments. Here, we have used two different antibody preparations against dystonin and detected a high-molecular-weight protein in immunoblot analysis of spinal cord extracts. We also show that this high-molecular-weight protein was not detectable in the nervous system of all dt alleles tested. Immunohistochemical analysis revealed that dystonin was present in different compartments of neurons--cell bodies, dendrites, and axons, regions which are rich in the three elements of the cytoskeleton (F-actin, neurofilaments, and microtubules). Ultrastructural analysis of dt dorsal root axons revealed disorganization of the neurofilament network and surprisingly also of the microtubule network. In this context it is of interest that we observed altered levels of the microtubule-associated proteins MAP2 and tau in spinal cord neurons of different dt alleles. Finally, dt dorsal root ganglion neurons formed neurites in culture, but the cytoskeleton was disorganized within these neurites. Our results demonstrate that dystonin is essential for maintaining neuronal cytoskeleton integrity but is not required for establishing neuronal morphology.
Topics: Animals; Animals, Newborn; Carrier Proteins; Cells, Cultured; Cytoskeletal Proteins; Cytoskeleton; Dystonin; Ganglia, Spinal; Immune Sera; Immunohistochemistry; Mice; Mice, Neurologic Mutants; Microtubule-Associated Proteins; Molecular Weight; Nerve Tissue Proteins; Nervous System; Neurons; Organ Specificity; Rats
PubMed: 9604204
DOI: 10.1006/mcne.1997.0660 -
Experimental Dermatology Jan 2016Since the immunochemical identification of the bullous pemphigoid antigen 230 (BP230) as one of the major target autoantigens of bullous pemphigoid (BP) in 1981, our... (Review)
Review
Since the immunochemical identification of the bullous pemphigoid antigen 230 (BP230) as one of the major target autoantigens of bullous pemphigoid (BP) in 1981, our understanding of this protein has significantly increased. Cloning of its gene, development and characterization of animal models with engineered gene mutations or spontaneous mouse mutations have revealed an unexpected complexity of the gene encoding BP230. The latter, now called dystonin (DST), is composed of at least 100 exons and gives rise to three major isoforms, an epithelial, a neuronal and a muscular isoform, named BPAG1e (corresponding to the original BP230), BPAG1a and BPAG1b, respectively. The various BPAG1 isoforms play a key role in fundamental processes, such as cell adhesion, cytoskeleton organization, and cell migration. Genetic defects of BPAG1 isoforms are the culprits of epidermolysis bullosa and complex, devastating neurological diseases. In this review, we summarize recent advances of our knowledge about several BPAG1 isoforms, their role in various biological processes and in human diseases.
Topics: Animals; Autoantigens; Cell Adhesion; Cell Movement; Cytoskeleton; Dystonin; Epithelial Cells; Exons; Gene Expression Profiling; Gene Expression Regulation; Homeostasis; Humans; Immunohistochemistry; Mice; Muscle, Skeletal; Muscles; Mutation; Neurons; Pemphigoid, Bullous; Plakins; Protein Domains; Protein Isoforms
PubMed: 26479498
DOI: 10.1111/exd.12877 -
Molecular Biology of the Cell Feb 2012Dystonin/Bpag1 is a cytoskeletal linker protein whose loss of function in dystonia musculorum (dt) mice results in hereditary sensory neuropathy. Although loss of...
Dystonin/Bpag1 is a cytoskeletal linker protein whose loss of function in dystonia musculorum (dt) mice results in hereditary sensory neuropathy. Although loss of expression of neuronal dystonin isoforms (dystonin-a1/dystonin-a2) is sufficient to cause dt pathogenesis, the diverging function of each isoform and what pathological mechanisms are activated upon their loss remains unclear. Here we show that dt(27) mice manifest ultrastructural defects at the endoplasmic reticulum (ER) in sensory neurons corresponding to in vivo induction of ER stress proteins. ER stress subsequently leads to sensory neurodegeneration through induction of a proapoptotic caspase cascade. dt sensory neurons display neurodegenerative pathologies, including Ca(2+) dyshomeostasis, unfolded protein response (UPR) induction, caspase activation, and apoptosis. Isoform-specific loss-of-function analysis attributes these neurodegenerative pathologies to specific loss of dystonin-a2. Inhibition of either UPR or caspase signaling promotes the viability of cells deficient in dystonin. This study provides insight into the mechanism of dt neuropathology and proposes a role for dystonin-a2 as a mediator of normal ER structure and function.
Topics: Animals; Apoptosis; Calcium; Carrier Proteins; Caspases; Cytoskeletal Proteins; Dystonia Musculorum Deformans; Dystonin; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Enzyme Activation; Mice; Mice, Mutant Strains; Nerve Tissue Proteins; Neurons; Protein Isoforms; Unfolded Protein Response
PubMed: 22190742
DOI: 10.1091/mbc.E11-06-0573