Title

Evaluation of LRRK2 Transgenic Mice as a Novel Model of Parkinson’s Disease.

Publication/Presentation Date

11-19-2008

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are an important cause of late-onset, autosomal dominant Parkinson’s disease (PD), and also contribute to sporadic disease. The G2019S mutation has been identified as the most common cause of familial and sporadic PD known to date. LRRK2-linked PD is characterized by the degeneration of nigral dopaminergic neurons and gliosis together with pleomorphic neuropathology including Lewy bodies, tau-positive inclusions, ubiquitin-positive inclusions or the distinct absence of protein inclusions. LRRK2 pathogenic variants induce marked neuronal toxicity in vitro consistent with a toxic gain-of-function mechanism for mutations. To explore the potentially detrimental properties of disease-associated LRRK2 mutations in vivo we have developed multiple lines of transgenic mice expressing full-length wild-type, R1441C and G2019S human LRRK2 from a novel hybrid CMV-enhanced human PDGF-beta promoter. LRRK2 mice are viable, fertile, and survive into adulthood. Transgenic mice express LRRK2 widely throughout the brain including the substantia nigra, striatum and cerebral cortex. LRRK2 transgenic mice fail to develop obvious pathological protein inclusions or aggregates such as alpha-synuclein, tau, ubiquitin or silver-positive inclusions up to 18-21 months of age. Behaviorally, R1441C and G2019S mutant LRRK2 mice exhibit normal locomotor activity in the open field at 6 months of age, whereas G2019S mice display impairments in pre-pulse inhibition of the acoustic startle response. Intriguingly, transgenic mice expressing wild-type LRRK2 exhibit a mild loss of nigral dopaminergic neurons as assessed by unbiased stereology of TH-positive neurons at 18-21 months of age. These phenotypic studies are ongoing. Thus, LRRK2 transgenic mice driven by a CMV-enhanced human PDGF-beta promoter may represent a promising model of LRRK2-linked PD and will provide important insight into the molecular mechanism(s) underlying LRRK2-induced neurodegeneration.

ISSN

832.24/L10

Comments

Program#/Poster#: 832.24/ L10

Disciplines

Medical Pathology | Pathology

Department(s)

Department of Pathology and Laboratory Medicine, Pathology Laboratory Medicine Faculty

Document Type

Presentation

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