title: Neurodegenerative phenotypes in an A53T α-synuclein transgenic mouse model are independent of LRRK2.
abstract: Mutations in the genes encoding LRRK2 and α-synuclein cause autosomal dominant forms of familial Parkinson's disease (PD). Fibrillar forms of α-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, α-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 α-synuclein to regulate its aggregation. To explore the potential pathophysiological interaction between LRRK2 and α-synuclein in vivo, we modulated LRRK2 expression in a well-established human A53T α-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 α-synuclein transgenic mice, including premature lethality, pre-symptomatic behavioral deficits and human α-synuclein or glial neuropathology. We also find that endogenous or human LRRK2 and A53T α-synuclein do not interact together to influence the number of nigrostriatal dopaminergic neurons. Taken together, our data suggest that α-synuclein-related pathology, which occurs predominantly in the hindbrain of this A53T α-synuclein mouse model, occurs largely independently from LRRK2 expression. These observations fail to provide support for a pathophysiological interaction of LRRK2 and α-synuclein in vivo, at least within neurons of the mouse hindbrain.
authors.affiliation: NeuroRegeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: João Paulo L
authors.initials: JP
authors.lastname: Daher
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.forename: Alessandra
authors.initials: A
authors.lastname: Musso
authors.forename: Sandra
authors.initials: S
authors.lastname: Gellhaar
authors.forename: Dagmar
authors.initials: D
authors.lastname: Galter
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.forename: Michael K
authors.initials: MK
authors.lastname: Lee
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Moore
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases