Neurodegenerative phenotypes in an A53T-synuclein transgenic mouse model are independent of LRRK2
Open Access
- 31 May 2012
- journal article
- research article
- Published by Oxford University Press (OUP) in Human Molecular Genetics
- Vol. 21 (11), 2420-2431
- https://doi.org/10.1093/hmg/dds057
Abstract
Mutations in the genes encoding LRRK2 and -synuclein cause autosomal dominant forms of familial Parkinsons disease (PD). Fibrillar forms of -synuclein are a major component of Lewy bodies, the intracytoplasmic proteinaceous inclusions that are a pathological hallmark of idiopathic and certain familial forms of PD. LRRK2 mutations cause late-onset familial PD with a clinical, neurochemical and, for the most part, neuropathological phenotype that is indistinguishable from idiopathic PD. Importantly, -synuclein-positive Lewy bodies are the most common pathology identified in the brains of PD subjects harboring LRRK2 mutations. These observations may suggest that LRRK2 functions in a common pathway with -synuclein to regulate its aggregation. To explore the potential pathophysiological interaction between LRRK2 and -synuclein in vivo, we modulated LRRK2 expression in a well-established human A53T -synuclein transgenic mouse model with transgene expression driven by the hindbrain-selective prion protein promoter. Deletion of LRRK2 or overexpression of human G2019S-LRRK2 has minimal impact on the lethal neurodegenerative phenotype that develops in A53T -synuclein transgenic mice, including premature lethality, pre-symptomatic behavioral deficits and human -synuclein or glial neuropathology. We also find that endogenous or human LRRK2 and A53T -synuclein do not interact together to influence the number of nigrostriatal dopaminergic neurons. Taken together, our data suggest that -synuclein-related pathology, which occurs predominantly in the hindbrain of this A53T -synuclein mouse model, occurs largely independently from LRRK2 expression. These observations fail to provide support for a pathophysiological interaction of LRRK2 and -synuclein in vivo, at least within neurons of the mouse hindbrain.This publication has 44 references indexed in Scilit:
- Enhanced Striatal Dopamine Transmission and Motor Performance with LRRK2 Overexpression in Mice Is Eliminated by Familial Parkinson's Disease Mutation G2019SJournal of Neuroscience, 2010
- Genome-wide association study reveals genetic risk underlying Parkinson's diseaseNature Genetics, 2009
- Mendelian forms of Parkinson's diseaseBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2009
- Molecular mechanisms of α-synuclein neurodegenerationBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2009
- The genetics of Parkinson's syndromes: a critical reviewCurrent Opinion in Genetics & Development, 2009
- The biology and pathobiology of LRRK2: Implications for Parkinson's diseaseParkinsonism & Related Disorders, 2008
- Lrrk2 and Lewy body diseaseAnnals of Neurology, 2006
- Parkinson's Disease α-Synuclein Transgenic Mice Develop Neuronal Mitochondrial Degeneration and Cell DeathJournal of Neuroscience, 2006
- Aβ deposition is associated with enhanced cortical α-synuclein lesions in Lewy body diseasesNeurobiology of Aging, 2005
- AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's diseaseNature Genetics, 1998