TDP-43 causes differential pathology in neuronal versus glial cells in the mouse brain
| Autor: | Liangxue Lai, Sen Yan, Xiao-Jiang Li, Wenjie Wei, Shihua Li, Chuan-En Wang, Marta A. Gaertig |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Pathology
medicine.medical_specialty Leupeptins Transgene Mutant Mutation Missense Gene Expression Mice Transgenic Biology medicine.disease_cause PC12 Cells chemistry.chemical_compound MG132 Gene expression mental disorders Genetics medicine Animals Humans Molecular Biology Genetics (clinical) Neurons Mutation HEK 293 cells Amyotrophic Lateral Sclerosis nutritional and metabolic diseases Brain General Medicine Articles Phenotype Molecular biology nervous system diseases Rats DNA-Binding Proteins Mice Inbred C57BL medicine.anatomical_structure HEK293 Cells chemistry nervous system Proteolysis Neuroglia Proteasome Inhibitors |
| Zdroj: | Human molecular genetics. 23(10) |
| ISSN: | 1460-2083 |
| Popis: | Mutations in TAR DNA-binding protein 43 (TDP-43) are associated with familial forms of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Although recent studies have revealed that mutant TDP-43 in neuronal and glial cells is toxic, how mutant TDP-43 causes primarily neuronal degeneration in an age-dependent manner remains unclear. Using adeno-associated virus (AAV) that expresses mutant TDP-43 (M337V) ubiquitously, we found that mutant TDP-43 accumulates preferentially in neuronal cells in the postnatal mouse brain. We then ubiquitously or selectively expressed mutant TDP-43 in neuronal and glial cells in the striatum of adult mouse brains via stereotaxic injection of AAV vectors and found that it also preferentially accumulates in neuronal cells. Expression of mutant TDP-43 in neurons in the striatum causes more severe degeneration, earlier death and more robust symptoms in mice than expression of mutant TDP-43 in glial cells; however, aging increases the expression of mutant TDP-43 in glial cells, and expression of mutant TDP-43 in older mice caused earlier onset of phenotypes and more severe neuropathology than that in younger mice. Although expression of mutant TDP-43 in glial cells via stereotaxic injection does not lead to robust neurological phenotypes, systemic inhibition of the proteasome activity via MG132 in postnatal mice could exacerbate glial TDP-43-mediated toxicity and cause mice to die earlier. Consistently, this inhibition increases the expression of mutant TDP-43 in glial cells in mouse brains. Thus, the differential accumulation of mutant TDP-43 in neuronal versus glial cells contributes to the preferential toxicity of mutant TDP-43 in neuronal cells and age-dependent pathology. |
| Databáze: | OpenAIRE |
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