Parkinson's disease (PD) is a common neurodegenerative disease where the causes of the disease are unknown for ~90% of cases. However, a variety of genetic mutations cause PD in ~10% cases. Among the genetic causes of PD, autosomal dominant forms of familial PD (FPD) share many of the pathological and clinical features with more common late onset sporadic PD. Recently, mutations in LRRK2 gene were shown to cause late-onset FPD with variable penetrance and a-synuclein (a-Syn) pathology (a-synucleinopathy). Thus, PD caused by LRRK2 may involve interactions with environmental and genetic factors. To understand the pathogenic involvement of LRRK2 in causing PD with a-synucleinopathy, we have generated conditional human LRRK2 (hLRRK2) transgenic (Tg) mouse model where high-levels of mutant (R1441C and G2019S) and wild type (WT) hLRRK2 expression can be achieved in subcortical regions. We will determine that when expressed in subcortical neurons, mutant hLRRK2 causes progressive neuropathology in mice, including the loss of dopaminergic neurons. Because only ~50% of mutant hLRRK2 carriers develop PD within 70 years of age, mutant hLRRK2 may combine with other factors to fully express the pathogenic potential. We will test this hypothesis by testing whether mutant hLRRK2 increases vulnerability in dopaminergic neurons to dopaminergic toxin. Further, we will determine whether there is a pathologic interaction between mutant hLRRK2 and a-Syn in causing neurodegeneration of PD relevant neuronal populations.
Mutations in LRRK2 are the most common genetic cause of late onset PD and resemble sporadic PD. By producing and studying transgenic mouse model with LRRK2-dependent neurodegeneration, we hope to gain new insights about the pathogenesis of PD. Such information will lead to novel therapeutic targets for PD.
|Daniel, Guillaume; Moore, Darren J (2015) Modeling LRRK2 Pathobiology in Parkinson's Disease: From Yeast to Rodents. Curr Top Behav Neurosci 22:331-68|
|Tsika, Elpida; Moore, Darren J (2013) Contribution of GTPase activity to LRRK2-associated Parkinson disease. Small GTPases 4:164-70|
|Colla, Emanuela; Jensen, Poul H; Pletnikova, Olga et al. (2012) Accumulation of toxic ?-synuclein oligomer within endoplasmic reticulum occurs in ?-synucleinopathy in vivo. J Neurosci 32:3301-5|
|Colla, Emanuela; Coune, Philippe; Liu, Ying et al. (2012) Endoplasmic reticulum stress is important for the manifestations of ?-synucleinopathy in vivo. J Neurosci 32:3306-20|
|Tsika, Elpida; Moore, Darren J (2012) Mechanisms of LRRK2-mediated neurodegeneration. Curr Neurol Neurosci Rep 12:251-60|
|Daher, João Paulo L; Pletnikova, Olga; Biskup, Saskia et al. (2012) Neurodegenerative phenotypes in an A53T ?-synuclein transgenic mouse model are independent of LRRK2. Hum Mol Genet 21:2420-31|
|Tuite, Paul J; Mangia, Silvia; Tyan, Andrew E et al. (2012) Magnetization transfer and adiabatic R 1? MRI in the brainstem of Parkinson's disease. Parkinsonism Relat Disord 18:623-5|