Glial elements contribute to stress-induced torsinA expression in the CNS and peripheral nervous system

Abstract

DYT1 dystonia is caused by a single GAG deletion in Exon 5 of TOR1A, the gene encoding torsinA, a putative chaperone protein. In this study, central and peripheral nervous system perturbations (transient forebrain ischemia and sciatic nerve transection, respectively) were used to examine the systems biology of torsinA. After forebrain ischemia, quantitative real-time RT-PCR identified increased torsinA transcript levels in hippocampus, cerebral cortex, thalamus, striatum, and cerebellum at 24 h and 7 d. Expression declined toward sham values by 14 d in striatum, thalamus and cortex, and by 21 d in cerebellum and hippocampus. TorsinA transcripts were localized to dentate granule cells and pyramidal neurons in control hippocampus and were moderately elevated in these cell populations at 24 h after ischemia, after which CA1 expression was reduced, consistent with the loss of this vulnerable neuronal population. Increased in situ hybridization signal in CA1 stratum radiatum, stratum lacunosum-moleculare, and stratum oriens at 7 d after ischemia was correlated with the detection of torsinA immunoreactivity in interneurons and reactive astrocytes at 7 and 14 days. Sciatic nerve transection increased torsinA transcript levels between 24 h and 7 days in both ipsilateral and contralateral dorsal root ganglia (DRG). However, increased torsinA immunoreactivity was localized to both ganglion cells and satellite cells in ipsilateral DRG but was restricted to satellite cells contralaterally. These results suggest that torsinA participates in the response of neural tissue to central and peripheral insults and its sustained up-regulation indicates that torsinA may contribute to remodeling of neuronal circuitry. The striking induction of torsinA in astrocytes and satellite cells points to the potential involvement of glial elements in the pathobiology of DYT1 dystonia. KeywordsDYT1; dystonia; reactive astrocytes; hippocampus; satellite cells; dorsal root ganglia DYT1 dystonia obeys an autosomal dominant inheritance pattern with reduced penetrance, usually begins in childhood and frequently generalizes. The causal mutation is a GAG deletion in the TOR1A gene that removes a single glutamic acid residue near the carboxy terminus of the encoded protein torsinA (Ozelius et al., 1997;Ozelius et al., 1999 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Neuwald et al., 1999;Kamm et al., 2004;Callan et al., 2007). Members of the AAA+ family function as molecular chaperones for protein quality control (protein complex assembly, operation, disassembly, protein folding, unfolding, and degrad...

TorsinA participates in endoplasmic reticulum-associated degradation

“…high body temperature, oxidative stress, trauma or exposure to specific drugs, neurons in DYT1 carriers may experience toxic effects that compromise their function and alter neurotransmission 44 . As a corollary, ischemia or resection of nervous tissue in experimental animals results in upregulation of torsinA transcription, possibly as a compensatory mechanism 45 . Second, a number of studies have implicated torsinA in processing proteins through the secretory pathway, showing that reduced torsinA, the presence of torsinAΔE or abnormally high levels of wild-type torsinA can interfere with protein processing 13,14,15 .…”

Convergent evidence for abnormal striatal synaptic plasticity in dystonia

“…TorsinA is an ATP-binding protein, and the striatum is particularly metabolically active. The plastic changes in response to forebrain ischemia involves an increase in torsinA transcript levels over several days in striatum and, possibly, remodeling of basal ganglia circuits (Zhao et al, 2008b). The striatum is particularly sensitive to metabolic challenge (Nishino et al, 2000) and stroke, vascular malformation, or perinatal asphyxia (Bressman, 2000) can induce secondary dystonias.…”

The Genetics of Dystonias

“…The chaperone functions of torsinA may be essential during developmental processes, which seemingly involve interaction with cytoskeletal elements (Ferrari-Toninelli et al , 2004; Hewett et al , 2006; Kamm et al , 2004). The expression of torsinA shows prolonged increases after insults to the central nervous system (CNS) and peripheral nervous system (Zhao et al , 2008). Moreover, expression of torsinA in reactive astrocytes in the CNS and satellite cells in the peripheral nervous system indicates that glial cells may contribute to the pathobiology of DYT1 dystonia (Zhao et al , 2008).…”

“…The expression of torsinA shows prolonged increases after insults to the central nervous system (CNS) and peripheral nervous system (Zhao et al , 2008). Moreover, expression of torsinA in reactive astrocytes in the CNS and satellite cells in the peripheral nervous system indicates that glial cells may contribute to the pathobiology of DYT1 dystonia (Zhao et al , 2008). …”