| First Author | Daher JP | Year | 2012 |
| Journal | Hum Mol Genet | Volume | 21 |
| Issue | 11 | Pages | 2420-31 |
| PubMed ID | 22357653 | Mgi Jnum | J:183780 |
| Mgi Id | MGI:5319260 | Doi | 10.1093/hmg/dds057 |
| Citation | Daher JP, et al. (2012) Neurodegenerative phenotypes in an A53T alpha-synuclein transgenic mouse model are independent of LRRK2. Hum Mol Genet 21(11):2420-31 |
| abstractText | Mutations in the genes encoding LRRK2 and alpha-synuclein cause autosomal dominant forms of familial Parkinson's disease (PD). Fibrillar forms of alpha-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, alpha-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 alpha-synuclein to regulate its aggregation. To explore the potential pathophysiological interaction between LRRK2 and alpha-synuclein in vivo, we modulated LRRK2 expression in a well-established human A53T alpha-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 alpha-synuclein transgenic mice, including premature lethality, pre-symptomatic behavioral deficits and human alpha-synuclein or glial neuropathology. We also find that endogenous or human LRRK2 and A53T alpha-synuclein do not interact together to influence the number of nigrostriatal dopaminergic neurons. Taken together, our data suggest that alpha-synuclein-related pathology, which occurs predominantly in the hindbrain of this A53T alpha-synuclein mouse model, occurs largely independently from LRRK2 expression. These observations fail to provide support for a pathophysiological interaction of LRRK2 and alpha-synuclein in vivo, at least within neurons of the mouse hindbrain. |
