Loss of tyrosine hydroxylase, motor deficits and elevated iron in a mouse model of phospholipase A2G6-associated neurodegeneration (PLAN)
| Autor: | Patrick B. Walter, Michael Minkley, Raad Nashmi, Christopher K. Anderson, Patrick MacLeod |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Tyrosine 3-Monooxygenase Neurodegeneration with brain iron accumulation Iron Neuroaxonal Dystrophies Substantia nigra Basal Ganglia Mice 03 medical and health sciences 0302 clinical medicine Internal medicine Basal ganglia medicine Animals Molecular Biology Tyrosine hydroxylase business.industry Dopaminergic Neurons General Neuroscience Dopaminergic Neurodegeneration medicine.disease Substantia Nigra Disease Models Animal 030104 developmental biology Endocrinology medicine.anatomical_structure Motor Skills Peripheral nervous system Neurology (clinical) Motor Deficit business 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Brain Research. 1748:147066 |
| ISSN: | 0006-8993 |
| DOI: | 10.1016/j.brainres.2020.147066 |
| Popis: | Phospholipase A2G6-associated neurodegeneration (PLAN) is a rare early-onset monogenic neurodegenerative movement disorder which targets the basal ganglia and other regions in the central and peripheral nervous system; presenting as a series of heterogenous subtypes in patients. We describe here a B6.C3-Pla2g6m1J/CxRwb mouse model of PLAN which presents with early-onset neurodegeneration at 90 days which is analogous of the disease progression that is observed in PLAN patients. Homozygous mice had a progressively worsening motor deficit, which presented as tremors starting at 65 days and progressed to severe motor dysfunction and increased falls on the wire hang test at 90 days. This motor deficit positively correlated with a reduction in tyrosine hydroxylase (TH) protein expression in dopaminergic neurons of the substantia nigra (SN) without any neuronal loss. Fluorescence imaging of Thy1-YFP revealed spheroid formation in the SN. The spheroids in homozygous mice strongly mirrors those observed in patients and were demonstrated to correlate strongly with the motor deficits as measured by the wire hang test. The appearance of spheroids preceded TH loss and increased spheroid numbers negatively correlated with TH expression. Perls/DAB staining revealed the presence of iron accumulation within the SN of mice. This mouse model captures many of the major hallmarks of PLAN including severe-early onset neurodegeneration, a motor deficit that correlates directly to TH levels, spheroid formation and iron accumulation within the basal ganglia. Thus, this mouse line is a useful tool for further research efforts to improve understanding of how these disease mechanisms give rise to the disease presentations seen in PLAN patients as well as to test novel therapies. |
| Databáze: | OpenAIRE |
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