Neuroprotective Function of Cellular Prion Protein in a Mouse Model of Amyotrophic Lateral Sclerosis

Abstract

Transgenic mice expressing human mutated superoxide dismutase 1 (SOD1) linked to familial forms of amyotrophic lateral sclerosis are frequently used as a disease model. We used the SOD1 G93A mouse in a crossbreeding strategy to study the function of physiological prion protein (Prp). SOD1 G93APrp؊/؊ mice exhibited a significantly reduced life span, and an earlier onset and accelerated progression of disease, as compared with SOD1 G93APrp؉/؉ mice. Additionally, during disease progression, SOD1 G93APrp؊/؊ mice showed impaired rotarod performance, lower body weight, and reduced muscle strength. Histologically, SOD1 G93APrp؊/؊ mice showed reduced numbers of spinal cord motor neurons and extended areas occupied by large vacuoles early in the course of the disease. Analysis of spinal cord homogenates revealed no differences in SOD1 activity. Using an unbiased proteomic approach, a marked reduction of glial fibrillary acidic protein and enhanced levels of collapsing response mediator protein 2 and creatine kinase were detected in SOD1 G93A Prp؊/؊ versus SOD1 G93A mice. In the course of disease , Bcl-2 decreases , nuclear factor-B increases , and Akt is activated , but these changes were largely unaffected by Prp expression. Exclusively in double-transgenic mice , we detected a significant increase in extracellular signal-regulated kinase 2 activation at clinical onset. We propose that Prp has a beneficial role in the SOD1 G93A amyotrophic lateral sclerosis mouse model by influencing neuronal and/or glial factors involved in antioxidative defense , rather than anti- Amyotrophic lateral sclerosis is characterized by rapid degeneration of motor neurons in the spinal cord, brain stem, and cortical Betz cells. As a result, focal muscle wasting, weakness, and spasticity develop focally. These symptoms ultimately lead to global paralysis. Patients usually die due to respiratory failure within 3 years of symptom onset. The causes of ALS are diverse; 10 to 15% of cases are familial with autosomal dominant inheritance, and 20% of these are related to point mutations in the gene encoding Cu/Zn superoxide dismutase 1 (SOD1). SOD1 is a ubiquitously expressed homodimeric protein that catalyzes the reaction of O 2 Ϫ to O 2 and H 2 O 2 , which is then further metabolized by glutathione peroxidase. Mice overexpressing human mutated SOD1 (muSOD1) linked to ALS, develop disease resembling ALS in humans by a toxic gain of function.2 Several properties of muSOD1 were proposed to contribute to toxic gain of function, including enhanced peroxidase activity and formation of peroxynitrite, changes in copper and zinc binding, and aggregation of the enzyme. ALS progression is accompanied by oxidative stress processes, glutamate-induced excitotoxicity, cytoskeletal abnormalities, inflammatory processes, and toxicity via extracellular muSOD1.2,3 The apoptotic cascade is activated in the ALS model, shown by sequential activation of caspase-1 and Ϫ3.4 Interestingly, Bcl-2 overexpression had a neuroprotective effect and, like intrathecal administrati...

Allosteric function and dysfunction of the prion protein

“…Accordingly, it was recently shown that hop/STI1 enhanced self-renewal of stem/progenitor cells through its interaction with PrP C , and, again, the hop/STI1 230-245 peptide by itself had no effect [179]. A likely explanation for these data is that signaling leading to proliferation of either the glioma or the stem/progenitor [230][231][232][233][234][235][236][237][238][239][240][241][242][243][244][245] to PrP C . The flexible N-terminal tail was omitted for clarity; d, e lowresolution models (sets of grey spheres) of either hop/STI1 alone (d), or the hop/STI1:PrP C complex (e), generated from SAXS measurements, reveal a compaction of the tertiary structure of hop/STI1 upon binding to PrP C (arrow points to PrP C , where the globular domain is shown in yellow and the flexible N-terminal tail is shown in pink).…”

Protease-resistant SOD1 aggregates in amyotrophic lateral sclerosis demonstrated by Paraffin Embedded Tissue (PET) blot

“…Mice at terminal disease stage were anesthetized and transcardially perfused with PBS for cryoconservation of the tissue or by PBS followed by paraformaldehyde in case of subsequent paraffin embedding as published elsewhere [16]. Prepared were the spinal cords as well as the whole brains separated sagittally into the two hemispheres.…”

Mass spectrometry imaging (MSI) of metals in mouse spinal cord by laser ablation ICP-MS

“…Recently, some of us investigated the neuroprotective function of cellular prion protein in a mouse model of SOD1 linked amyotrophic lateral sclerosis which was characterized by rapid degeneration of motor neurons in spinal cord. 3 Due to the small sample size (2-5 mm 2 ) investigation of the metal distribution in mouse spinal cord requires powerful quantitative imaging techniques with higher spatial resolution than required for brain. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) as elemental mass spectrometry has been established for bioimaging of trace metals, especially for the essential transition metals Fe, Cu, Zn, and of selected non-metals (such as C, P and S) in our BrainMet (Bioimaging of Metals in Brain and Metallomics) laboratory at Forschungszentrum Ju¨lich.…”

“…A series of recent and ongoing studies has assessed pain, inflammatory or degenerative pathophysiology. [1][2][3] Popular animal models which have been assessed in this scope were unilateral limb lesions, experimental autoimmune encephalomyelitis (EAE) or animals transgenic for proteins involved in redox and free radical metabolism. In several cases where the systemic central nervous system is affected the pathology of the spinal cord is most informative and the brain only a side scene.…”