Immunocytochemical characterization of torsin proteins in mouse brain

Konakova, Marina; Pulst, Stefan M.

doi:10.1016/s0006-8993(01)03014-1

Cited by 49 publications

(35 citation statements)

References 21 publications

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“…In these and other studies, it is apparent that torsinA undergoes anterograde transport along neuronal processes to terminals, presumably in association with the ER and/or vesicles (12,(57)(58)(59), apparently mediated by kinesin. Ultrastructural studies in primate brain demonstrated torsinA immunoreactivity associated with small clear vesicles in symmetric synapses in the striatum (59).…”

Section: Nx(t/s) Asnmentioning

confidence: 54%

The Early Onset Dystonia Protein TorsinA Interacts with Kinesin Light Chain 1

Kamm

Boston

Hewett

et al. 2004

Journal of Biological Chemistry

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Early onset dystonia is a movement disorder caused by loss of a glutamic acid residue (Glu 302/303 ) in the carboxyl-terminal portion of the AAA ؉ protein, torsinA. We identified the light chain subunit (KLC1) of kinesin-I as an interacting partner for torsinA, with binding occurring between the tetratricopeptide repeat domain of KLC1 and the carboxyl-terminal region of torsinA. Coimmunoprecipitation analysis demonstrated that wildtype torsinA and kinesin-I form a complex in vivo. In cultured cortical neurons, both proteins co-localized along processes with enrichment at growth cones. Wildtype torsinA expressed in CAD cells co-localized with endogenous KLC1 at the distal end of processes, whereas mutant torsinA remained confined to the cell body. Subcellular fractionation of adult rat brain revealed torsinA and KLC associated with cofractionating membranes, and both proteins were co-immunoprecipitated after cross-linking cytoplasmically oriented proteins on isolated rat brain membranes. These studies suggest that wild-type torsinA undergoes anterograde transport along microtubules mediated by kinesin and may act as a molecular chaperone regulating kinesin activity and/or cargo binding.

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Section: Nx(t/s) Asnmentioning

confidence: 54%

The Early Onset Dystonia Protein TorsinA Interacts with Kinesin Light Chain 1

Kamm

Boston

Hewett

et al. 2004

Journal of Biological Chemistry

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“…In addition, recent evidence indicates that a significant pool of torsinA exhibits a topology in which the AAA ϩ domain faces the cytoplasm (20). In support of this topology, torsinA is found in the cytoplasm, neuronal processes, and synaptic terminals (2,3,15,(23)(24)(25)(26) and has been shown to bind cytosolic proteins snapin (27) and kinesin light chain 1 (20). TorsinA has been proposed to play a role in several cellular processes, including dopaminergic neurotransmission (28 -31), NE organization and dynamics (17,22,32), and protein trafficking (27,33).…”

mentioning

confidence: 89%

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Giles

Chin

2009

Journal of Biological Chemistry

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Early onset generalized dystonia (DYT1) is an autosomal dominant neurological disorder caused by deletion of a single glutamate residue (torsinA ⌬E) in the C-terminal region of the AAA ؉ (ATPases associated with a variety of cellular activities) protein torsinA. The pathogenic mechanism by which torsinA ⌬E mutation leads to dystonia remains unknown. Here we report the identification and characterization of a 628-amino acid novel protein, printor, that interacts with torsinA. Printor co-distributes with torsinA in multiple brain regions and colocalizes with torsinA in the endoplasmic reticulum. Interestingly, printor selectively binds to the ATP-free form but not to the ATP-bound form of torsinA, supporting a role for printor as a cofactor rather than a substrate of torsinA. The interaction of printor with torsinA is completely abolished by the dystoniaassociated torsinA ⌬E mutation. Our findings suggest that printor is a new component of the DYT1 pathogenic pathway and provide a potential molecular target for therapeutic intervention in dystonia.Early onset generalized torsion dystonia (DYT1) is the most common and severe form of hereditary dystonia, a movement disorder characterized by involuntary movements and sustained muscle spasms (1). This autosomal dominant disease has childhood onset and its dystonic symptoms are thought to result from neuronal dysfunction rather than neurodegeneration (2, 3). Most DYT1 cases are caused by deletion of a single glutamate residue at positions 302 or 303 (torsinA ⌬E) of the 332-amino acid protein torsinA (4). In addition, a different torsinA mutation that deletes amino acids Phe 323 -Tyr 328(torsinA ⌬323-328) was identified in a single family with dystonia (5), although the pathogenic significance of this torsinA mutation is unclear because these patients contain a concomitant mutation in another dystonia-related protein, ⑀-sarcoglycan (6). Recently, genetic association studies have implicated polymorphisms in the torsinA gene as a genetic risk factor in the development of adult-onset idiopathic dystonia (7,8).TorsinA contains an N-terminal endoplasmic reticulum (ER) 3 signal sequence and a 20-amino acid hydrophobic region followed by a conserved AAA ϩ (ATPases associated with a variety of cellular activities) domain (9, 10). Because members of the AAA ϩ family are known to facilitate conformational changes in target proteins (11,12), it has been proposed that torsinA may function as a molecular chaperone (13,14). TorsinA is widely expressed in brain and multiple other tissues (15) and is primarily associated with the ER and nuclear envelope (NE) compartments in cells (16 -20). TorsinA is believed to mainly reside in the lumen of the ER and NE (17-19) and has been shown to bind lamina-associated polypeptide 1 (LAP1) (21), lumenal domain-like LAP1 (LULL1) (21), and nesprins (22). In addition, recent evidence indicates that a significant pool of torsinA exhibits a topology in which the AAA ϩ domain faces the cytoplasm (20). In support of this topology, torsinA is found in the...

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“…In mammals, torsinA is widely expressed both in brain and peripheral tissues, showing a particularly high level of expression in dopaminergic neurons of the sub-stantia nigra pars compacta (Shashidharan et al, 2000a;Konakova and Pulst, 2001;Rostasy et al, 2003), indicative of dysfunction in dopaminergic transmission in dystonia patients (Shashidharan et al, 2000a).…”

Section: Introductionmentioning

confidence: 99%

Down‐regulation of torp4a, encoding the Drosophila homologue of torsinA, results in increased neuronal degeneration

Muraro

Moffat

2006

J. Neurobiol.

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Early-onset torsion dystonia is a dominant motor disorder linked to mutations in torsinA. TorsinA is weakly related to a superfamily of chaperone-like proteins. The function of the torsin group remains largely unknown. Here we use RNAi and over-expression to analyze the function of torp4a, the only Drosophila torsin. Targeted down-regulation in the eye causes progressive degeneration of the retina. Conversely, over-expression of torp4a protects from age-related degeneration. In the retinas of young animals, a correlation with the lysosome-related organelle, the pigment granule, is also observed. Lowering torp4a causes an increase in pigment granules, while over-expression causes loss of granules. We have performed a screen for genetic interactors of torp4a identifying a number mutants, including two members of the AP-3 complex. Other genetic interactors found included genes related to actin and myosin function. Our findings implicate the Drosophila torsin, torp4a, to function with molecules consistent with already predicted roles in the endoplasmic reticulum/nuclear envelope compartment, and have identified potential new interactions with AP-3 like components.

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Immunocytochemical characterization of torsin proteins in mouse brain

Cited by 49 publications

References 21 publications

The Early Onset Dystonia Protein TorsinA Interacts with Kinesin Light Chain 1

The Early Onset Dystonia Protein TorsinA Interacts with Kinesin Light Chain 1

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Down‐regulation of torp4a, encoding the Drosophila homologue of torsinA, results in increased neuronal degeneration

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