Phenotypic Characterization of BAC LRRK2 Transgenic Pre-clinical Models
MJFF Research Grant, 2011
Mutations in the protein leucine-rich repeat kinase 2 (LRRK2) are the most common cause of inherited Parkinson’s disease (PD). Interestingly, the penetrance LRRK2 mutations and the associated pathology are variable. Thus, there remains much to be learned on the role of LRRK2 mutations in PD. The main goals of this work are to characterize the behavioral, neurochemical, and pathological features of pre-clinical models expressing LRRK2 mutations that are known to cause PD in humans.
To determine whether pre-clinical models expressing mutations in LRRK2 exhibit features of human PD, experiments examining behavior, neurochemistry, and pathology will be conducted in pre-clinical models aged 4, 8, and 12 months. Motor deficits will be assessed using neurobehavioral tests. The integrity of the nigrostriatal dopamine system will be assessed by examination of striatal dopamine levels, dopamine terminal density, and nigral dopamine cell loss. The accumulation of α-synuclein in nigral dopamine neurons – a pathological hallmark of human PD will be determined. Additionally, the pathological features of these pre-clinical models, including examination of mitochondrial morphology and evidence oxidative stress will be characterized. Finally, whether these mutations confer increased sensitivity to the environmental neurotoxicant, rotenone will be determined to help understand gene-environment interactions that may precipitate PD in humans.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Characterization of these pre-clinical models is expected to increase our understanding of the behavioral and pathological features associated with LRRK2 mutations. Such experiments may lead to the identification of new diagnostic indicators in humans with these mutations. Further, these pre-clinical models may be useful in assessing novel therapeutic approaches.
We expect to learn if these new pre-clinical models replicate the key features of human PD. Additionally, we expect to learn more about the relationship between specific LRRK2 mutations and pathology, which will be of great use, given that pathological data on LRRK2 mutations is limited and variably reported in humans. We will also learn if having these mutations may increase sensitivity to environmental neurotoxicants.
LRRK2 mutations are the most common genetic form of PD. We characterized 2 new genetic models of PD – pre-clinical models that express either the G2019S or the R1441G mutation of the LRRK2 gene. While the pre-clinical models did not show behaviors similar to PD and did not show degeneration of their dopamine neurons, they did show early abnormalities of these cells, which suggested that they were under stress. Thus, these pre-clinical models appear to show very early signs of LRRK2-associated disease. As such, they may be useful for studying interactions between genetic and environmental factors that cause PD.
Director, Pittsburgh Institute for Neurodegenerative Diseases at University of Pittsburgh
Location: Pittsburgh, Pennsylvania, United States