Thomas Brännström - Academia.edu (original) (raw)

Papers by Thomas Brännström

Research paper thumbnail of Motor Neuron Disease in Mice Expressing the Wild Type-Like D90A Mutant Superoxide Dismutase-1

Journal of Neuropathology and Experimental Neurology, 2006

Mutant human CuZn-superoxide dismutases (hSOD1s) cause amyotrophic lateral sclerosis (ALS). The m... more Mutant human CuZn-superoxide dismutases (hSOD1s) cause amyotrophic lateral sclerosis (ALS). The most common mutation is the wild type-like D90A and to explore its properties, transgenic mice were generated and compared with mice expressing wild-type hSOD1. D90A hSOD1 was both in vivo in mice and in vitro under denaturing conditions nearly as stable as the wild-type human enzyme. It appeared less toxic than other tested mutants, but mice homozygous for the transgene insertion developed a fatal motor neuron disease. In these mice, the disease progression was slow and there were bladder disturbances similar to what is found in human ALS cases homozygous for the D90A mutation. The homozygous D90A mice accumulated detergent-resistant hSOD1 aggregates in spinal cords, and abundant hSOD1 inclusions and vacuoles were seen in the ventral horns. Mice expressing wild-type hSOD1 at a comparable rate showed similar pathologic changes but less and later. Hemizygous D90A mice showed even milder alterations. At 600 days, the wild-type hSOD1 transgenic mice had lost more ventral horn neurons than hemizygous D90A mice (38% vs 31% p G 0.01). Thus, wild-type hSOD1 shows a significant neurotoxicity in the spinal cord, that is less than equal but more than half as large as that of D90A mutant enzyme.

Research paper thumbnail of Glial nuclear aggregates of superoxide dismutase-1 are regularly present in patients with amyotrophic lateral sclerosis

Acta Neuropathologica, 2011

The most common cause of amyotrophic lateral sclerosis (ALS) is mutations in superoxide dismutase... more The most common cause of amyotrophic lateral sclerosis (ALS) is mutations in superoxide dismutase-1 (SOD1). Since there is evidence for the involvement of non-neuronal cells in ALS, we searched for signs of SOD1 abnormalities focusing on glia. Spinal cords from nine ALS patients carrying SOD1 mutations, 51 patients with sporadic or familial ALS who lacked such mutations, and 46 controls were examined by immunohistochemistry. A set of anti-peptide antibodies with specificity for misfolded SOD1 species was used. Misfolded SOD1 in the form of granular aggregates was regularly detected in the nuclei of ventral horn astrocytes, microglia, and oligodendrocytes in ALS patients carrying or lacking SOD1 mutations. There was negligible staining in neurodegenerative and nonneurological controls. Misfolded SOD1 appeared occasionally also in nuclei of motoneurons of ALS patients. The results suggest that misfolded SOD1 present in glial and motoneuron nuclei may generally be involved in ALS pathogenesis.

Research paper thumbnail of Superoxide dismutase-1 and other proteins in inclusions from transgenic amyotrophic lateral sclerosis model mice

Journal of Neurochemistry, 2010

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by l... more Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by loss of motor neurons in the motor cortex, brainstem, and spinal cord. This results in progressive muscular atrophy, and the patients usually succumb to respiratory failure within a few years. About 10% of ALS cases appear in families (Haverkamp et al. 1995), and in some of these the disease is linked to mutations in the gene of the ubiquitously expressed antioxidant enzyme CuZn-superoxide dismutase (SOD1) (Rosen et al. 1993). Overall, about 6% of all cases with ALS show SOD1 mutations, and more than 140 such mutations have been identified [(Andersen et al. 2003); http://alsod.iop.kcl.ac.uk/ Als/Summary/summary.aspx]. The mutations confer a cytotoxic gain of function of unknown character to the enzyme (Gurney et al. 1994; Andersen et al. 1995). There is now considerable evidence to suggest that the demise of motor neurons is non-cell autonomous and dependent on noxious effects of mutant SOD1s in several cell types in the motor areas (Boillee et al. 2006; Nagai et al. 2007; Henkel et al. 2009). A hallmark of ALS caused by mutant SOD1s, both in patients and transgenic models, is inclusions that are immunoreactive for SOD1 (Bruijn et al. 1997; Johnston et al. 2000; Jonsson et al. 2004, 2006b). In the animal models, inclusions appear concomitantly with the onset of symptoms and become markedly more abundant in the terminal phase of the disease (Johnston et al. 2000; Wang et al. 2002b; Jonsson et al. 2004, 2006a). They are present in

Research paper thumbnail of Motor Neuron Disease in Mice Expressing the Wild Type-Like D90A Mutant Superoxide Dismutase-1

Journal of Neuropathology and Experimental Neurology, 2006

Mutant human CuZn-superoxide dismutases (hSOD1s) cause amyotrophic lateral sclerosis (ALS). The m... more Mutant human CuZn-superoxide dismutases (hSOD1s) cause amyotrophic lateral sclerosis (ALS). The most common mutation is the wild type-like D90A and to explore its properties, transgenic mice were generated and compared with mice expressing wild-type hSOD1. D90A hSOD1 was both in vivo in mice and in vitro under denaturing conditions nearly as stable as the wild-type human enzyme. It appeared less toxic than other tested mutants, but mice homozygous for the transgene insertion developed a fatal motor neuron disease. In these mice, the disease progression was slow and there were bladder disturbances similar to what is found in human ALS cases homozygous for the D90A mutation. The homozygous D90A mice accumulated detergent-resistant hSOD1 aggregates in spinal cords, and abundant hSOD1 inclusions and vacuoles were seen in the ventral horns. Mice expressing wild-type hSOD1 at a comparable rate showed similar pathologic changes but less and later. Hemizygous D90A mice showed even milder alterations. At 600 days, the wild-type hSOD1 transgenic mice had lost more ventral horn neurons than hemizygous D90A mice (38% vs 31% p G 0.01). Thus, wild-type hSOD1 shows a significant neurotoxicity in the spinal cord, that is less than equal but more than half as large as that of D90A mutant enzyme.

Research paper thumbnail of Glial nuclear aggregates of superoxide dismutase-1 are regularly present in patients with amyotrophic lateral sclerosis

Acta Neuropathologica, 2011

The most common cause of amyotrophic lateral sclerosis (ALS) is mutations in superoxide dismutase... more The most common cause of amyotrophic lateral sclerosis (ALS) is mutations in superoxide dismutase-1 (SOD1). Since there is evidence for the involvement of non-neuronal cells in ALS, we searched for signs of SOD1 abnormalities focusing on glia. Spinal cords from nine ALS patients carrying SOD1 mutations, 51 patients with sporadic or familial ALS who lacked such mutations, and 46 controls were examined by immunohistochemistry. A set of anti-peptide antibodies with specificity for misfolded SOD1 species was used. Misfolded SOD1 in the form of granular aggregates was regularly detected in the nuclei of ventral horn astrocytes, microglia, and oligodendrocytes in ALS patients carrying or lacking SOD1 mutations. There was negligible staining in neurodegenerative and nonneurological controls. Misfolded SOD1 appeared occasionally also in nuclei of motoneurons of ALS patients. The results suggest that misfolded SOD1 present in glial and motoneuron nuclei may generally be involved in ALS pathogenesis.

Research paper thumbnail of Superoxide dismutase-1 and other proteins in inclusions from transgenic amyotrophic lateral sclerosis model mice

Journal of Neurochemistry, 2010

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by l... more Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by loss of motor neurons in the motor cortex, brainstem, and spinal cord. This results in progressive muscular atrophy, and the patients usually succumb to respiratory failure within a few years. About 10% of ALS cases appear in families (Haverkamp et al. 1995), and in some of these the disease is linked to mutations in the gene of the ubiquitously expressed antioxidant enzyme CuZn-superoxide dismutase (SOD1) (Rosen et al. 1993). Overall, about 6% of all cases with ALS show SOD1 mutations, and more than 140 such mutations have been identified [(Andersen et al. 2003); http://alsod.iop.kcl.ac.uk/ Als/Summary/summary.aspx]. The mutations confer a cytotoxic gain of function of unknown character to the enzyme (Gurney et al. 1994; Andersen et al. 1995). There is now considerable evidence to suggest that the demise of motor neurons is non-cell autonomous and dependent on noxious effects of mutant SOD1s in several cell types in the motor areas (Boillee et al. 2006; Nagai et al. 2007; Henkel et al. 2009). A hallmark of ALS caused by mutant SOD1s, both in patients and transgenic models, is inclusions that are immunoreactive for SOD1 (Bruijn et al. 1997; Johnston et al. 2000; Jonsson et al. 2004, 2006b). In the animal models, inclusions appear concomitantly with the onset of symptoms and become markedly more abundant in the terminal phase of the disease (Johnston et al. 2000; Wang et al. 2002b; Jonsson et al. 2004, 2006a). They are present in