Table 1
Genotype-dependent Subcellular Distributions of Overexpressed Human TorsinA Proteins in Mammalian Systems
| Cell Type/Name | WT-torsinA | ΔE-torsinA | References |
|---|---|---|---|
| Cultured non-neuronal cells | |||
| Human astrocytes (brain region, not specified) | Diffuse cytoplasmic (colocalized with GFAP) | (–) | Armata et al.76 |
| Human fibroblasts | Diffuse cytoplasmic (colocalized with PDI); no TEM abnormality of nuclear envelope | Inclusions; abnormal TEM of nuclear envelope | Hettich et al.77 |
| Human glioma Gli36 cells | Diffuse cytoplasmic (colocalized with PDI); perinuclear staining | Inclusions; perinuclear | Bragg et al.78 |
| Human glioma Gli36 cells | Diffuse cytoplasmic; perinuclear (colocalized with laminB, nucleoporin) | Perinuclear (colocalized with laminB, nucleoporin); with/without inclusions (not colocalized with laminB or nucleoporin), depending on expression levels | Bragg et al.16 |
| Human osteosarcoma U2OS cells | Diffuse cytoplasmic; minimal inclusions (<5% of cells) | Inclusions (∼90% of cells); not perinuclear | Kock et al.79 |
| Human osteosarcoma U2OS cells | Diffuse cytoplasmic; minimal perinuclear | Diffuse cytoplasmic; perinuclear; no inclusions | Vander Heyden et al.80 |
| Human osteosarcoma U2OS cells | Diffuse cytoplasmic | (–) | Naismith et al.81 |
| Human osteosarcoma U2OS cells | Diffuse cytoplasmic (excluded from ER exit sites) | (–) | Vander Heyden et al.82 |
| Human adenocarcinoma HeLa cells | Diffuse cytoplasmic (colocalized with KDEL) | Same as WT-torsinA overexpression | Giles et al.26 |
| Human adenocarcinoma HeLa cells | Diffuse cytoplasmic; minimal perinuclear | Inclusions; minimal perinuclear | Zhu et al.83 |
| Human embryonic kidney epithelial HEK293 cells | Diffuse cytoplasmic (colocalized with GRP78/BiP); perinuclear | Inclusions (not colocalized with GRP78/BiP); not perinuclear | Kustedjo et al.19 |
| Human embryonic kidney epithelial HEK293 cells | Diffuse cytoplasmic (colocalized with PDI) | Inclusions (in>95% of cells) | O’Farrell et al.21,84 |
| Human embryonic kidney epithelial HEK293 cells | Diffuse cytoplasmic | Inclusions; overexpressed ΔE-torsinA recruits overexpressed WT-torsinA to inclusions | Torres et al.85 |
| Human embryonic kidney epithelial HEK293 cells | Diffuse cytoplasmic | Inclusions; these form whether or not torsinA has a carboxy-terminal V5-His-tag | Grundmann et al.15 |
| Human embryonic kidney epithelial HEK293 cells | Diffuse cytoplasmic | (–) | Armata et al.76 |
| Human embryonic kidney epithelial HEK293 cells | (–) (no light-microscopic data; normal TEM of nuclear envelope) | (–) (no light-microscopic data; abnormal TEM of nuclear envelope) | Zirn et al.86 |
| Human embryonic kidney epithelial HEK293 cells | Diffuse cytoplasmic | Inclusions; overexpressed ΔE-torsinA recruits overexpressed WT-torsinA to inclusions | O’Farrell et al.68 |
| Human embryonic kidney epithelial 293T cells | Diffuse cytoplasmic (colocalized with PDI) | Inclusions | Hettich et al.77 |
| African green monkey kidney fibroblast-like COS-7 cells | Diffuse cytoplasmic (colocalized with GRP78/BiP); perinuclear; (N-terminus was modified to increase expression level in Kustedjo et al.87) | Inclusions (not colocalized with GRP78/BiP); not perinuclear; (N-terminus was modified to increase expression level in Kustedjo et al.87) | Kustedjo et al.19,87 |
| African green monkey kidney fibroblast-like COS-7 cells | Diffuse cytoplasmic (colocalized with PDI) | Perinuclear; inclusions (not colocalized with PDI) | Naismith et al.18 |
| African green monkey kidney fibroblast-like COS-7 cells | Diffuse cytoplasmic | Inclusions | Torres et al.85 |
| African green monkey kidney fibroblast-like COS-7 cells | Diffuse cytoplasmic; minimal perinuclear | Inclusions; minimal perinuclear | Zhu et al.83 |
| African green monkey kidney fibroblast-like COS-7 cells | Diffuse cytoplasmic (colocalized with PDI) | (–) | Nery et al.88 |
| African green monkey kidney fibroblast-like COS-7 cells | Diffuse cytoplasmic (only partly colocalized with calreticulin, the soluble lumenal protein present throughout the ER, indicating that torsinA prefers ER flat sheet to ER tubules) | (–) | Vander Heyden et al.82 |
| African green monkey kidney fibroblast-like COS-1 cells | Diffuse cytoplasmic | (–) | Shashidharan et al.48 |
| African green monkey kidney epithelial Vero cells | Diffuse cytoplasmic (colocalized with KDEL); weak perinuclear | (–) | Maric et al.89 |
| Mouse fibroblast NIH-3T3 cells | Diffuse cytoplasmic | Perinuclear | Jungwirth et al.90 |
| Baby hamster kidney fibroblast BHK21 cells | Diffuse cytoplasmic (colocalized with KDEL); weak perinuclear (∼20% of cells); no inclusions (∼0%) | Perinuclear (∼70% of cells); with/without inclusions (inclusions in ∼70% of cells), depending on expression levels; overexpressed ΔE-torsinA recruits overexpressed WT-torsinA to perinuclear distribution | Goodchild and Dauer10 |
| Baby hamster kidney fibroblast BHK21 cells | Diffuse cytoplasmic | Perinuclear; with/without diffuse cytoplasmic staining, depending on expression levels | Goodchild and Dauer91 |
| Baby hamster kidney fibroblast BHK21 cells | Diffuse cytoplasmic (colocalized with KDEL in 100% of cells); inclusions (10% of cells); minimal perinuclear (colocalized with laminB1 in 6% of cells) | Inclusions (79% of cells; inclusions were smaller than those in overexpressed WT-torsinA); colocalized with laminB1 in 89%; colocalized with KDEL in 12%; not colocalized with lysosomal or autophagosomal markers | Calakos et al.92 |
| Baby hamster kidney fibroblast BHK21 cells | Diffuse cytoplasmic (colocalized with PDI); perinuclear (not colocalized with PDI) | (–) | Jungwirth et al.65 |
| Baby hamster kidney fibroblast BHK21 cells | Diffuse cytoplasmic | Perinuclear | Jungwirth et al.90 |
| Chinese hamster ovary epithelial-like CHO cells | Diffuse cytoplasmic | Perinuclear; with/without inclusions, depending on expression levels | Naismith et al.18 |
| Chinese hamster ovary epithelial-like CHO cells | Diffuse cytoplasmic (porcine torsinA) | Same as WT-torsinA overexpression (porcine torsinA) | Henriksen et al.93 |
| Chinese hamster ovary epithelial-like CHO cells | Diffuse cytoplasmic (colocalized with GRP78/BiP) | (–) | Josse et al.94 |
| Rat oligodendrocyte OLN cells | Punctate (porcine torsinA) | Same as WT-torsinA overexpression (porcine torsinA) | Henriksen et al.93 |
| Cultured neuronal tumor cells | |||
| Human neuroblastoma SH-SY5Y cells | Diffuse cytoplasmic (colocalized with PDI) | Inclusions (colocalized with VMAT2 but not with PDI); not perinuclear | Misbahuddin et al.17 |
| Human neuroblastoma SH-SY5Y cells (differentiated) | Diffuse cytoplasmic | Perinuclear; inclusions | Hewett et al.40 |
| Human neuroblastoma SH-SY5Y cells | Diffuse cytoplasmic (colocalized with PDI) | Perinuclear; inclusions (colocalized with snapin) | Granata et al.37 |
| Human neuroblastoma SH-SY5Y cells | Diffuse cytoplasmic (colocalized with KDEL); perinuclear | Diffuse cytoplasmic (colocalized with KDEL); more preferential perinuclear staining than with WT-torsinA | Giles et al.26,95 |
| Human neuroblastoma SH-SY5Y cells | Diffuse cytoplasmic (porcine torsinA) | Diffuse cytoplasmic; ring-like inclusions (porcine torsinA) | Henriksen et al.93 |
| Human neuroblastoma SH-SY5Y cells | Diffuse cytoplasmic (excluding nucleoplasm) | Perinuclear; inclusions | Granata et al.38 |
| Human neuroblastoma SH-SY5Y cells | Diffuse cytoplasmic (colocalized with PDI); no inclusions (found in ∼4% of cells) | Inclusions (found in ∼100% of cells); minimally colocalized with PDI | Vulinovic et al.96 |
| Human neuroblastoma SK-N-AS cells | Diffuse cytoplasmic; minimal inclusions (∼15% of cells); minimal perinuclear | Inclusions (∼90% of cells); perinuclear | Cheng et al.97 |
| Human neuroblastoma BE(2)-C cells (undifferentiated and differentiated) | Diffuse cytoplasmic (colocalized with PDI) | Inclusions | Hettich et al.77 |
| Mouse neuroblastoma N2A cells | Diffuse cytoplasmic | (–) | Armata et al.76 |
| Mouse neural line CAD cells (differentiated) | Punctate cytoplasmic in cell body and neurite (colocalized with PDI, partially with VAMP2); not perinuclear | Inclusions (colocalized with PDI, but not with VAMP2 or GM130); not perinuclear; TEM shows torsinA and PDI in inclusions | Hewett et al.20 |
| Mouse neural line CAD cells | Diffuse cytoplasmic in cell body and process | Inclusions (colocalized with KLC in 57% of cells) | Kamm et al.36 |
| Mouse neural line CAD cells | (–) | Perinuclear; inclusions | Naismith et al.18 |
| Mouse neural line CAD cells | Diffuse cytoplasmic; minimal inclusions (<5% of cells) | Inclusions (∼85% of cells); not perinuclear | Kock et al.79 |
| Rat pheochromocytoma PC12 cells | Diffuse cytoplasmic (colocalized with PDI) | Perinuclear; inclusions (not colocalized with PDI) | Naismith et al.18 |
| Rat pheochromocytoma PC12 cells | Diffuse cytoplasmic | Inclusions | Torres et al.85 |
| Rat pheochromocytoma PC6-3 cells (differentiated) | Diffuse cytoplasmic (colocalized with GRP78/BiP, calnexin) | Perinuclear (colocalized with laminA); inclusions (colocalized with laminA/C, laminB, emerin, etc.) | Gonzalez-Alegre and Paulson67 |
| Rat pheochromocytoma PC6-3 cells | Diffuse cytoplasmic | Inclusions; overexpressed ΔE-torsinA recruits overexpressed WT-torsinA to inclusions | Gonzalez-Alegre et al.63 |
| Rat pheochromocytoma PC6-3 cells | Diffuse cytoplasmic | Perinuclear; inclusions | Gordon and Gonzalez-Alegre,23 Gordon et al.,73 Maric et al.,89 Martin et al.98 |
| Cultured neurons | |||
| Mouse midbrain neurons (including substantia nigra, ventral tegmental area) | Diffuse cytoplasmic in soma and process; inclusions (∼5% of all neurons, ∼0% of TH-negative neurons, ∼20% of TH-positive neurons) | Inclusions (54% of all neurons, 43% of TH-negative neurons, 84% of TH-positive neurons) (colocalized with TH, but not with PDI) (TH-positive neurons comprised 20–30% of all neurons) | O'Farrell et al.68 |
| Mouse cerebral cortical neurons (7 DIV) | Diffuse cytoplasmic in soma and process | Perinuclear | Nery et al.88 |
| Rat dorsal root ganglion neurons (3 DIV) | Diffuse cytoplasmic in soma; minimal perinuclear (4% of neurons); no inclusions (0% of neurons) | Diffuse cytoplasmic in soma; perinuclear (58%); inclusions (28%) | Kock et al.99 |
| Neurons in situ | |||
| Transgenic mouse, neurons in cerebral cortex | Diffuse cytoplasmic (colocalized with KDEL) | Perinuclear (colocalized with laminB1) | Goodchild and Dauer10 |
| Transgenic mouse, neurons in striatum | Diffuse/punctate cytoplasmic; no inclusions; not perinuclear; ∼twofold increase in torsinA protein level in comparison to non-transgenic control mice | Same as in transgenic mice overexpressing WT-torsinA or non-transgenic control; ∼twofold increase in torsinA protein level in comparison to non-transgenic control mice | Sharma et al.14 |
| Transgenic mouse, neurons in periaqueductal gray, pedunculopontine nucleus, pons | (–) | Inclusions (colocalized with lamin A/C, ubiquitin); these changes were absent in cerebral cortex, hippocampus, striatum, substantia nigra pars compacta, cerebellar cortex | Shashidharan et al.100 |
| Transgenic mouse, neurons in substantia nigra, raphe nucleus, pedunculopontine nucleus, cerebellar cortex, deep cerebellar nuclei, gigantocellular reticular nucleus | Diffuse cytoplasmic in soma and dendrite; inclusions (colocalized with lamin A/C, ubiquitin-protein conjugates, but not with PDI) (inclusions not found in hippocampus, striatum, substantia nigra, cerebellar cortex); ∼sixfold increase in human protein level from non-transgenic mice; high expression caused TEM abnormality of nuclear envelope (30% of neurons in striatum, 10–20% of brainstem neurons) | Similar to WT-torsinA overexpression; ∼twofold increase in human protein level from non-transgenic mice; TEM nuclear envelope abnormality more frequent than in WT-torsinA overexpression (∼50% of neurons in striatum, 30–40% of brainstem neurons) | Grundmann et al.15 |
| Transgenic mouse, neurons in cerebral cortex, striatum, substantia nigra pars compacta, pontine nuclei | Diffuse cytoplasmic in soma and proximal dendrite; no perinuclear; no inclusions; human torsinA transcript was not increased in comparison to control human brains; no TEM abnormality of nuclear envelope in striatum, pontine nuclei, cerebellar cortex, spinal cord | Same as WT-torsinA overexpression and non-transgenic control; human torsinA transcript was four-to-fivefold higher than in control human brains; no TEM abnormality of nuclear envelope in striatum, pontine nuclei, cerebellar cortex, spinal cord | Zhao et al.27 (same mice as reported in Sharma et al.14) |
| Transgenic mouse, neurons in olfactory bulb | Diffuse cytoplasmic in soma and dendrite; inclusions in mitral cell; no staining in dentate gyrus of hippocampus or striatum | (–) | Regensburger et al.101 (same mice as reported in Grundmann et al.15) |
| Transgenic mouse, neurons in striatum (medium spiny neurons) | Diffuse/punctate cytoplasmic in soma and proximal dendrite; no staining in nucleoplasm, fibers | Diffuse/punctate cytoplasmic in soma and proximal dendrite; no staining in nucleoplasm or fibers. | Martella et al.102 (same mice as reported in Sharma et al.14) |
| Transgenic mouse, neurons in substantia nigra pars compacta (dopaminergic neurons; human torsinA was overexpressed only in dopaminergic neurons using TH promoter) | Diffuse cytoplasmic in soma and proximal dendrite | Perinuclear | Page et al.24 |
| Transgenic mouse, neurons in striatum (cholinergic interneurons) | (–) | Same as in non-transgenic controls (diffuse cytoplasmic in soma and proximal dendrite) | Sciamanna et al.75 (same mice as reported in Sharma et al.14) |
| Transgenic rat, neurons in olfactory bulb, cerebral cortex, hippocampus, striatum, substantia nigra | Diffuse cytoplasmic in soma and proximal dendrite (not colocalized with lamin A/C that showed continuous curve); normal TEM of nuclear envelope; protein expression level was not specified for morphological studies | Perinuclear in a discontinuous pattern (colocalized with lamin A/C); abnormal TEM of nuclear envelope; not expressed in pons, cerebellum, brainstem; torsinA protein expression level was ∼sevenfold higher than the lowest expressing line | Grundmann et al.103 |
[i] In this article, “perinuclear” indicates ring-like staining of the nuclear envelope completely surrounding the nucleoplasm. “Inclusions” indicate intracellular, cytoplasmic inclusion bodies, except where intranuclear inclusion is specifically mentioned in Table 3. The cytoplasmic inclusions were often located near cellular nuclei. (–) indicates not tested.
[ii] Table 1 includes results with human torsinA, except for one study that analyzed porcine torsinA (mentioned as such).
[iii] Table 1 and Table 2 include both controlled and uncontrolled expression of the exogenous transgene.
[iv] In Tables 1–, 3, the results are limited to the distributions of wild-type and ΔE-torsinA. They do not include other naturally occurring mutations or genetically engineered proteins. Results from experimental manipulations that could affect the torsinA distribution were not included. Such manipulations are, e.g., the co-transfection with non-torsinA transgene constructs, the induction of cellular stress and ischemic insults, and the pharmacological regulation of biological processes.
[v] Abbreviations and comments in Tables 1–, 3: calbindin D-28K (Purkinje neuron marker); calnexin (ER marker); ChAT, Choline Acetyltransferase (cholinergic neuron marker); CSN4, COP9 signalosome complex subunit 4; DIV, Days In Vitro; EM, Electron Microscopy; emerin (nuclear envelope marker); ER, Endoplasmic Reticulum; GABA, γ-Aminobutyric Acid (inhibitory neurotransmitter); GFAP, Glial Fibrillary Acidic Protein (astrocyte marker); GM130, Golgi Matrix protein of 130 kDa (Golgi apparatus marker); GRP78/BiP, Glucose-Regulated Protein of 78 kDa/Binding Immunoglobulin Protein, also known as heat shock 70 kDa protein 5 (HSPA5) (ER marker); KDEL, Lysine-Aspartic Acid-Glutamic Acid-Leucine Sequence (ER retention signal); KLC, Kinesin Light Chain (motor protein); lamins (nuclear envelope markers); NOS, Nitric Oxide Synthase (marker of a class of GABAergic neurons); NSE, Neuron-Specific Enolase (neuronal marker); nucleoporin (nuclear envelope marker); parvalbumin (marker of a class of GABAergic neurons); PDI, Protein Disulfide Isomerase (ER marker); SGI, Secretogranin I (secretory granule marker); snapin (SNAP25 [synaptosomal associated protein of 25 kDa]-binding protein); somatostatin (marker of a class of GABAergic neurons); TEM, Transmission Electron Microscopy; TH, Tyrosine Hydroxylase (dopaminergic/noradrenergic neuron marker); VAMP2, Vesicle-Associated Membrane Protein/Synaptobrevin 2 (synaptic vesicle/nerve terminal marker); VGAT, Vesicular GABA Transporter (GABAergic nerve terminal marker); VGLUT1 and 2, Vesicular Glutamate Transporters 1 and 2 (glutamatergic nerve terminal markers); VMAT2, Vesicular Monoamine Transporter 2 (monoaminergic marker); WT, wild type; ΔE, deletion of a single GAG codon in TOR1A or Tor1a gene (associated with DYT1 dystonia).
Table 2
Subcellular Distributions of Human TorsinA Proteins at Different Overexpression Levels
| Cell type/name | WT-torsinA | ΔE-torsinA | References |
|---|---|---|---|
| Human glioma Gli36 cells (expression level was actively controlled by tetracycline-regulated system) | Unchanged pattern (diffuse cytoplasmic; weak perinuclear), irrespective of expression levels | Perinuclear when expression level is low to moderate (two- to 10-fold increase from endogenous level); additional inclusions when the level is high (∼20-fold increase from endogenous level) | Bragg et al.16 |
| Baby hamster kidney fibroblast BHK21 cells (expression level was monitored) | Unchanged pattern (diffuse cytoplasmic; weak perinuclear), irrespective of expression levels | Perinuclear when expression level is low to moderate; additional inclusions when the level is high | Goodchild and Dauer10 |
| Baby hamster kidney fibroblast BHK21 cells (expression level was monitored) | (–) | Perinuclear when the expression level is low; additional, diffuse cytoplasmic staining when the level is higher. | Goodchild and Dauer91 |
| Chinese hamster ovary epithelial-like CHO cells (expression level was monitored) | (–) | Perinuclear and diffuse cytoplasmic when expression level is low; additional inclusions when the level is high (e.g.>fourfold higher than the low expression) | Naismith et al.18 |
Table 3
Subcellular Localization of Endogenous TorsinA Proteins in Mammalian Systems
| Cell type/name | WT-torsinA | ΔE-torsinA | References |
|---|---|---|---|
| Cultured non-neuronal cells | |||
| Human fibroblasts | Diffuse/punctate cytoplasmic; minimal perinuclear | Strong perinuclear; weaker cytoplasmic; no inclusions; patients' cells (TOR1A+/ΔE) | Goodchild and Dauer10 |
| Human fibroblasts | Diffuse cytoplasmic; not perinuclear | Same as WT-torsinA; no inclusions; patients' cells (TOR1A+/ΔE) | Hewett et al.40 |
| Human fibroblasts | Diffuse cytoplasmic; minimal perinuclear | Same as WT-torsinA; no inclusions; patients' cells (TOR1A+/ΔE) | Nery et al.41 |
| Mouse embryonic fibroblasts | Diffuse cytoplasmic (partially colocalized with KDEL) | (–) | Giles et al.26 |
| Cultured neuronal tumor cells | |||
| Human neuroblastoma SH-SY5Y cells | Diffuse cytoplasmic in cell body; nucleoplasm | (–) | Hewett et al.66 |
| Human neuroblastoma SH-SY5Y cells (differentiated) | Punctate cytoplasmic in cell body; punctate accumulation in neurite varicosity (colocalized with VAMP) | (–) | Ferrari-Toninelli et al.35 |
| Human neuroblastoma SH-SY5Y cells | Diffuse cytoplasmic in cell body (colocalized with KDEL) (processes were not present) | (–) | Giles et al.95 |
| Human neuroblastoma SH-SY5Y cells | Punctate cytoplasmic in cell body and process (colocalized with CSN4) | (–) | Granata et al.38 |
| Human neuroglioma H4 cells | Diffuse cytoplasmic in cell body; no inclusions | (–) | McLean et al.104 |
| Rat pheochromocytoma PC12 cells (differentiated) | Diffuse cytoplasmic in cell body and process (colocalized with PDI) | (–) | Hewett et al.72 |
| Rat pheochromocytoma PC12 cells (differentiated) | Punctate accumulation in neurite tip (colocalized with snapin, SGI) | (–) | Granata et al.37 |
| Cultured neurons | |||
| Mouse cerebral cortical neurons | Diffuse cytoplasmic | (–) | Gonzalez-Alegre et al.63 |
| Mouse cerebral cortical neurons (3–7 DIV) | Diffuse cytoplasmic (colocalized with KDEL); some perinuclear (more localized to nuclear envelope than in embryonic fibroblasts in the same study) | (–) | Giles et al.26 |
| Mouse cerebral cortical neurons | Diffuse cytoplasmic | (–) | Kim et al.105 |
| Mouse hippocampal neurons (4 DIV) | Punctate cytoplasmic in soma and process (colocalized with snapin) | (–) | Granata et al.37 |
| Mouse cerebellar granule neurons (4–6 DIV) | Punctate cytoplasmic in soma and neurite (colocalized with CSN4) | (–) | Granata et al.38 |
| Mouse neurons from cerebral cortex, hippocampus, striatum, ΔE-torsinA knock-in model (12–16 DIV) | Proximal dendrite; absent from axon and nerve terminal; soma was not evaluated | Same as in WT-torsinA; (Tor1a+/ΔE and Tor1aΔE/ΔE) | Koh et al.39 |
| Rat cerebral cortical neurons (8 DIV) | Punctate cytoplasmic in soma, neurite, growth cone (colocalized with KLC1) | (–) | Kamm et al.36 |
| Neurons in situ | |||
| Human neurons in cerebral cortex, hippocampus, substantia nigra pars compacta | Diffuse cytoplasmic in soma, proximal dendrite; nucleoplasm; no staining of white matter | (–) | Shashidharan et al.48 |
| Human neurons in cerebral cortex, substantia nigra pars compacta (in Parkinson's disease) | Positive staining in intracellular Lewy bodies (that are positive for α-synuclein) | (–) | Shashidharan et al.69 |
| Human neurons in cerebral cortex, hippocampus, caudate-putamen, thalamus, substantia nigra pars compacta, oculomotor nucleus, cerebellar cortex, spinal cord | Diffuse/punctate cytoplasmic in soma, proximal dendrite; fibers in white matter, brachium of superior colliculus, etc; no staining of nucleoplasm | (–) | Konakova et al.42 |
| Human neurons in hippocampus, substantia nigra (in diffuse Lewy body disease) | No staining of soma or dendrite; positive staining in Lewy bodies (colocalized with α-synuclein and ubiquitin, but closely associated with only α-synuclein at <30-nm resolution). | (–) | Sharma et al.106 |
| Human neurons in substantia nigra (in dementia with Lewy body disease) | No staining of soma or dendrite; positive staining in Lewy bodies (colocalized with α-synuclein which in turn is colocalized with heat shock proteins) | (–) | McLean et al.104 |
| Human neurons in cerebral cortex, hippocampus, caudate-putamen, substantia nigra pars compacta, oculomotor nucleus, cerebellar cortex | Punctate cytoplasmic in soma (limited colocalization with PDI); proximal dendrite; nucleoplasm (sparing nucleoli); punctate neuropil (putative nerve terminals); no inclusions; not perinuclear | Same as in WT-torsinA; patient's brain (TOR1A+/ΔE) | Walker et al.49 |
| Human neurons in cerebral cortex, hippocampus, oculomotor nucleus (in Huntington's disease, spinocerebellar ataxia type III, and Huntington's disease-like 2 which had previously been diagnosed as chorea-acanthocytosis107) | Positive in intranuclear inclusion bodies (that are positive for ubiquitin, expanded polyglutamine repeats) | (–) | Walker et al.108,109 |
| Human neurons in hippocampus, caudate-putamen, nucleus basalis of Meynert, substantia nigra pars compacta, cerebellar cortex | Punctate cytoplasmic in soma, proximal dendrite; some axons and “pencil bundle fibers” (axons of medium spiny neurons in caudate-putamen); punctate neuropil (putative nerve terminals) | Same as in WT-torsinA; no inclusions; only caudate-putamen and substantia nigra pars compacta were analyzed in patients' brains (TOR1A+/ΔE) | Rostasy et al.44 |
| Human neurons in hippocampus, putamen, substantia nigra pars compacta, cerebellar cortex | No staining of soma or dendrite; punctate neuropil (putative axon, nerve terminals; vesicles in axons (immuno-EM). | (–) | Augood et al.46 |
| Human neurons in periaqueductal gray, pedunculopontine nucleus, cuneiform nucleus | No inclusions | Inclusions (colocalized with laminA/C, ubiquitin-protein conjugates, ubiquitin, but weakly with PDI); these inclusions were absent in cerebral cortex, hippocampus, striatum, substantia nigra pars compacta; patients' brains (TOR1A+/ΔE) | McNaught et al.50 |
| Human neurons in substantia nigra (in diffuse Lewy body disease) | Positive staining in Lewy bodies | (–) | O’Farrell et al.84 |
| Human neurons in hippocampus, putamen, globus pallidus, substantia nigra pars compacta, oculomotor nucleus, superior colliculus, cerebellar cortex, dentate nucleus of deep cerebellar nuclei, during development | Diffuse/punctate cytoplasmic in soma, proximal dendrite; putative axon and nerve terminal; no nucleoplasm; no staining before postnatal 6 weeks | (–) | Siegert et al.70 |
| Human neurons in pedunculopontine nucleus, cuneiform nucleus, pontine reticular formation (in normal subjects and patients with non-DYT1 dystonia) | No inclusions | (–) | Holton et al.110 |
| Patus monkey neurons in hippocampus | Nucleoplasm, axon, nerve terminal (immuno-EM); no other compartments were analyzed | (–) | Walker et al.43 |
| Macaque monkey neurons in putamen | No staining of soma or dendrite; staining in neuropil; vesicles in nerve terminals (immuno-EM). | (–) | Augood et al.46 |
| Mouse neurons in cerebral cortex, hippocampus, caudate-putamen, thalamus, substantia nigra pars compacta, motor nucleus of trigeminal nerve, cerebellar cortex | Strong staining of fibers in cerebral cortical white matter, corpus callosum, internal capsule, anterior commissure, cerebral peduncle, etc; diffuse/punctate cytoplasmic in soma, proximal dendrite | (–) | Konakova and Pulst45 |
| Mouse neurons in peri-aqueductal gray, pedunculopontine nucleus, pontine nuclei | Diffuse cytoplasmic in soma (colocalized with PDI, but not with lamin A/C or ubiquitin) | (–) | Shashidharan et al.100 |
| Mouse neurons in cerebral cortex, substantia nigra pars compacta, pontine nuclei of ΔE-torsinA knock-in model | Diffuse cytoplasmic in soma; no inclusions in brains of male or female mice | Inclusions only in pontine nuclei of male mice (colocalized with ubiquitin) (not found in female mice) (Tor1a+/ΔE) | Dang et al.111 |
| Mouse neurons in striatum (cholinergic interneurons) | Diffuse cytoplasmic in soma and proximal dendrite | (–) | Sciamanna et al.75 |
| Mouse neurons in cerebellar cortex, deep cerebellar nuclei | Diffuse/punctate cytoplasmic in soma, dendrite, dendritic spine (partially colocalized with calbindin D-28K, parvalbumin), nerve terminal (partially colocalized with VGLUT1, VGLUT2, VGAT); nucleoplasm of neurons expressing high level of torsinA | (–) | Puglisi et al.71 |
| Mouse neurons in red nucleus, interstitial nucleus of Cajal, of brain-restricted nestin-Cre Tor1aflox/ΔE model (“nestin selective knock-in” mouse) | Diffuse cytoplasmic (expression level was ∼60% of Tor1a+/ΔE mice) (nestin-Cre control mouse) | Perinuclear (expression level was ∼20% of Tor1a+/ΔE mice) (Tor1a−/ΔE) | Liang et al.61 |
| Rat neurons in hippocampus, substantia nigra pars compacta, cerebellar cortex, deep cerebellar nuclei | Nucleoplasm; diffuse cytoplasmic in soma, proximal dendrite (partially colocalized with TH) | (–) | Shashidharan et al.48 |
| Rat neurons in cerebral cortex, hippocampus, striatum, cerebellar cortex | Nucleoplasm (sparing nucleoli); diffuse cytoplasmic in soma (partially colocalized with NSE, NOS, parvalbumin, GABA or ChAT), proximal dendrites of some but not all neurons; punctate neuropil (putative nerve terminals) | (–) | Walker et al.47 |
| Rat neurons in cerebral cortex, hippocampus, striatum, substantia nigra pars compacta, cerebellar cortex | Diffuse cytoplasmic in soma, dendrite; not perinuclear or nucleoplasmic; punctate “pencil fiber bundle” axons in young striatum | (–) | Xiao et al.34 |
| Rat neurons in cerebral cortex, hippocampus, striatum, thalamus, during development | Cytoplasm in soma, processes; increased staining intensity during postnatal 7 to 28 days | (–) | Oberlin et al.112 |
| Rat neurons in striatum, globus pallidus, subthalamic nucleus | Nucleoplasm (sparing nucleoli); less strong in perikaryal cytoplasm and proximal dendrite | (–) | Yamada et al.113 |
| Rat neurons in hippocampus | Diffuse cytoplasmic in soma, proximal dendrite of pyramidal neurons and parvalbumin- or somatostatin-positive interneurons | (–) | Zhao et al.52 |
| Rat neurons in dorsal root ganglion | Diffuse cytoplasmic in soma; axon | (–) | Zhao et al.52 |
[i] Note that the cells of DYT1 dystonia patients are listed under “ΔE-torsinA.” However, they are heterozygous for the mutant allele (TOR1A+/ΔE), i.e., both wild-type and ΔE-torsinA proteins will be present. Similarly, heterozygous ΔE-torsinA knock-in mice (Tor1a+/ΔE) will express two types of full-length proteins. In contrast, the homozygous ΔE-torsinA knock-in mice (Tor1aΔE/ΔE) express only the ΔE-torsinA protein, and the brain-restricted nestin-Cre Tor1aflox/ΔE mice express the ΔE-torsinA protein and exons 1 and 2 (out of exons 1–5) of wild-type protein (i.e., effectively Tor1a−/ΔE).