Neuronal degeneration in autonomic nervous system of Dystonia musculorum mice

Abstract

Background: Dystonia musculorum (dt) is an autosomal recessive hereditary neuropathy with a characteristic uncoordinated movement and is caused by a defect in the bullous pemphigoid antigen 1 (BPAG1) gene. The neural isoform of BPAG1 is expressed in various neurons, including those in the central and peripheral nerve systems of mice. However, most previous studies on neuronal degeneration in BPAG1-deficient mice focused on peripheral sensory neurons and only limited investigation of the autonomic system has been conducted. Methods: In this study, patterns of nerve innervation in cutaneous and iridial tissues were examined using general neuronal marker protein gene product 9.5 via immunohistochemistry. To perform quantitative analysis of the autonomic neuronal number, neurons within the lumbar sympathetic and parasympathetic ciliary ganglia were calculated. In addition, autonomic neurons were cultured from embryonic dt/dt mutants to elucidate degenerative patterns in vitro. Distribution patterns of neuronal intermediate filaments in cultured autonomic neurons were thoroughly studied under immunocytochemistry and conventional electron microscopy. Results: Our immunohistochemistry results indicate that peripheral sensory nerves and autonomic innervation of sweat glands and irises dominated degeneration in dt/dt mice. Quantitative results confirmed that the number of neurons was significantly decreased in the lumbar sympathetic ganglia as well as in the parasympathetic ciliary ganglia of dt/dt mice compared with those of wild-type mice. We also observed that the neuronal intermediate filaments were aggregated abnormally in cultured autonomic neurons from dt/dt embryos. Conclusions: These results suggest that a deficiency in the cytoskeletal linker BPAG1 is responsible for dominant sensory nerve degeneration and severe autonomic degeneration in dt/dt mice. Additionally, abnormally aggregated neuronal intermediate filaments may participate in neuronal death of cultured autonomic neurons from dt/dt mutants.

Novel mutations in dystonin provide clues to the pathomechanisms of HSAN-VI

“…Our pathologic findings resembled those observed in footpad skin of young adult dt mice that showed a marked impairment of sweat gland sympathetic innervation. 37 Within the nervous system, the 3 major neuronal isoforms (dystonin-a1, -a2, -a3) are characterized by unique N-terminal regions that depend on alternative use of TSS in the first exons. 15 The uniqueness of each isoform dictates cellular localization and function.…”

Genetic pain loss disorders

“…Neuronal DST is a cytoskeletal linker protein that interacts with actin, microtubule networks and organelles. Moreover, DST has a role in endoplasmic reticulum (ER) structure and function and in autophagy in different cellular models; however, a direct link to ER-phagy has not been established [19][20][21][22][23][24][25] . DST has multiple tissue-specific isoforms , therefore, DST mutations are associated with various clinical manifestations, including dysautonomia with contractures, psychomotor retardation and motor neuropathy, but also autosomal-recessive epidermolysis bullosa simplex 26,27 .…”

Protective Effects of Fucoxanthin Dampen Pathogen-Associated Molecular Pattern (PAMP) Lipopolysaccharide-Induced Inflammatory Action and Elevated Intraocular Pressure by Activating Nrf2 Signaling and Generating Reactive Oxygen Species

“…Pupillary reactions were evaluated in unanesthetized rats following our previous protocol [29] with some modifications. Each rat was adapted to darkness for at least 45 min and subsequently placed on a custom-built stereotactic apparatus while their motion was confined using a 56 mm-diameter polyethylene tube.…”

“…To determine the extent of innervation, the iris tissues were collected for immunohistochemical analysis as described in our previous report [29]. Iridial whole-mount samples were transferred into PBS solution containing 3% hydrogen peroxide to eliminate endogenous peroxidase activity.…”