The pathogenic LRRK2 R1441C mutation induces specific deficits modeling the prodromal phase of Parkinson's disease in the mouse
| Autor: | Luise Ernst, D. M. Vogt Weisenhorn, Lisa Glasl, Annemarie Zimprich, Florian Giesert, G. Piccoli, Sabine M. Hölter, Julia Zerle, Wolfgang Wurst, C. Stautner |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Parkinson's disease Prodromal symptoms metabolism [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2] Behavioral phenotyping medicine.disease_cause Mice 0302 clinical medicine metabolism [Synaptotagmin I] genetics [Parkinson Disease] Neurodegenertion genetics [Point Mutation] psychology [Swimming] Gait genetics [Arginine] Genetics Mutation Gene knockdown Neurodegeneration Parkinson Disease LRRK2 Phenotype Smell Neurology Synaptotagmin I Genetic mouse model of Parkinson's disease physiopathology [Parkinson Disease] physiology [Recognition Psychology] Genotype Tyrosine 3-Monooxygenase genetics [Smell] genetics [Cysteine] Synaptophysin Prodromal Symptoms Mice Transgenic genetics [Motor Activity] Knock-out–knock-in models Motor Activity Biology Arginine Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 lcsh:RC321-571 03 medical and health sciences ddc:570 medicine Point Mutation Animals Cysteine lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Swimming Loss function Point mutation metabolism [Synaptophysin] Recognition Psychology medicine.disease pathology [Parkinson Disease] metabolism [Tyrosine 3-Monooxygenase] nervous system diseases Disease Models Animal 030104 developmental biology Exploratory Behavior genetics [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2] genetics [Gait] Neuroscience 030217 neurology & neurosurgery physiology [Exploratory Behavior] |
| Zdroj: | Neurobiology of Disease, Vol 105, Iss, Pp 179-193 (2017) Neurobiology of disease 105, 179-193 (2017). doi:10.1016/j.nbd.2017.05.013 |
| DOI: | 10.1016/j.nbd.2017.05.013 |
| Popis: | The aim of the present study was to further explore the in vivo function of the Leucine-rich repeat kinase 2 (LRRK2)-gene, which is mutated in certain familial forms of Parkinson's disease (PD). We generated a mouse model harboring the disease-associated point mutation R1441C in the GTPase domain of the endogenous murine LRRK2 gene (LRRK2 R1441C line) and performed a comprehensive analysis of these animals throughout lifespan in comparison with an existing knockdown line of LRRK2 (LRRK2 knockdown line). Animals of both lines do not exhibit severe motor dysfunction or pathological signs of neurodegeneration neither at young nor old age. However, at old age the homozygous LRRK2 R1441C animals exhibit clear phenotypes related to the prodromal phase of PD such as impairments in fine motor tasks, gait, and olfaction. These phenotypes are only marginally observable in the LRRK2 knockdown animals, possibly due to activation of compensatory mechanisms as suggested by in vitro studies of synaptic transmission. Thus, at the organismal level the LRRK2 R1441C mutation does not emerge as a loss of function of the protein, but induces mutation specific deficits. Furthermore, judged by the phenotypes presented, the LRRK2-R1441C knock-in line is a valid preclinical model for the prodromal phase of PD. |
| Databáze: | OpenAIRE |
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