Neurodegenerative Diseases by Daniela Galimberti & Elio Scarpini

Author:Daniela Galimberti & Elio Scarpini
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

Valosin-Containing Protein (VCP) Models

Mutations in the valosin-containing protein (VCP) gene are known to cause the multisystem degenerative disorder called inclusion body myopathy associated with Paget’s disease of the bone and frontotemporal dementia (IBMPFD) [166]. Although muscle weakness and myopathy are the most common clinical features of this disorder, approximately 30% of patients also develop language and behavioral impairments typical of FTLD [167]. Furthermore, TDP-43- and ubiquitin-positive inclusions are found in both the brain and muscle of IBMPFD patients. Interestingly, some reports also link VCP mutations to ALS [168, 169]. Over 20 mutations have been identified in VCP, all of which are thought to alter the 3D structure of VCP and thereby perturb the interactions between VCP and its various substrates [170]. Substitution of arginine 155 to histidine (R155H) is the mutation most commonly associated with IBMPFD. It is for this reason that the majority of mouse models utilize this particular mutation. Another mutation, A232E, is associated with a particularly severe clinical presentation in humans [166].

To develop an animal model of IBMPFD , a number of groups have generated transgenic mice that express mutant VCP [171–175]. Although these strains all express a similar mutant protein, there are a number of inherent differences amongst the strains. For example, because mouse VCP differs from the human protein by only one amino acid, some groups chose to express human mutant VCP in the mouse model, whereas other models express mutant mouse VCP. Various promoters have been used to generate mice that overexpress the mutant protein exclusively in muscle [172], the brain [171], or ubiquitous expression in all tissues [173], while other groups have generated knockin mice that express mutant VCP at levels similar to that of the endogenous protein [174, 175].

Despite these inherent differences, all mutant VCP mouse strains have been reported to develop VCP-negative, TDP-43-positive, and ubiquitin-positive aggregates. These aggregates develop in regions where the mutant protein is expressed, i.e., the muscle, brain, and spinal cord. In heterozygote animals, these aggregates appear at around 10–15 months in the muscle and the spinal cord and at 14–20 months in the brain, while in homozygous mice [175], TDP-43 aggregates were observed as early as 15 days in the muscle, brain, and spinal cord. In some strains, cytoplasmic and nuclear clearance of TDP-43 was observed, as well as insoluble and high molecular weight TDP-43 species [171, 173, 176]. In one particular strain, TDP-43 aggregates were observed to co-localize with the stress granule marker TIA-1, and overall levels of TIA-1 were increased, suggesting an increased stress response, which could potentially alter mRNA transport and translation. Altered stress granule dynamics and/or altered mRNA metabolism may therefore play a role in the disease processes associated with TDP-43 proteinopathies. Despite the presence of TDP-43 aggregates, none of the strains show any sign of neurodegeneration in the brain [171, 173, 174], although loss of motor neurons in the spinal cord has been reported [176].

Other pathological features commonly observed in these mice include a significant increase in the levels of general protein

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