Neurodegenerative phenotypes in an A53T  -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.

Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents

“…It is noteworthy that in human PD, these brain areas are also dense with α-synuclein containing Lewy bodies and Lewy neurites, the primary pathological hallmarks of PD (Churchyard and Lees, 1997;Duda et al, 2002;Braak et al, 2003). Recent emerging evidence suggests interactions between LRRK2 and α-synuclein aggregation (Lin et al, 2009;Orenstein et al, 2013), but this remains controversial (Daher et al, 2012;Herzig et al, 2012). Thus, the cortico-striatal circuit may in part be selectively vulnerable in PD because of the concentration of proteins known to underlie aspects of late-onset PD.…”

Abrogation of α-synuclein–mediated dopaminergic neurodegeneration in LRRK2-deficient rats

“…The absence of LRRK2 has been shown to impair α-synuclein inclusion formation, neuron loss, and microglia activation in mice overexpressing mutant α-synuclein (7). However, other studies that have crossed LRRK2 knockout mice with different α-synuclein transgenic mice did not observe robust protection from the formation of α-synuclein pathology or differences in animal survival rates (8,9). Because these α-synuclein transgenic mice do not have loss of dopaminergic neurons in the SNpc, it is not known whether LRRK2 may modify α-synucleinmediated dopaminergic cell loss and associated critical phenotypes relevant to PD.…”

Modeling LRRK2 Pathobiology in Parkinson’s Disease: From Yeast to Rodents

“…We and others do not observe a pathological interaction between human LRRK2 and a-synuclein when employing alternative A53T a-synuclein transgenic mice driven by the hindbrain-selective PrP or broadly expressing Thy1 promoters (Daher et al 2012;Herzig et al 2012). Both studies demonstrate that high levels of G2019S LRRK2 expression within neurons of the cortex, striatum, brainstem, and spinal cord of mice do not exacerbate a-synuclein-mediated neuropathology.…”

“…The consequences of LRRK2 deletion on motor deficits induced by A53T a-synuclein were not reported ). In a subsequent study, Daher and colleagues employed an A53T a-synuclein transgenic mouse model under the control of the hindbrain-selective mouse prion protein (PrP) promoter to explore the pathological interaction between LRRK2 and a-synuclein (Daher et al 2012). The deletion of LRRK2 did not influence the lethal neurodegenerative phenotype of PrP-A53T asynuclein transgenic mice, including premature survival, behavioral deficits, asynuclein pathology and gliosis, suggesting that a-synuclein-mediated neurodegeneration in hindbrain neurons occurs largely independent of LRRK2 expression in mice (Daher et al 2012).…”

“…In a subsequent study, Daher and colleagues employed an A53T a-synuclein transgenic mouse model under the control of the hindbrain-selective mouse prion protein (PrP) promoter to explore the pathological interaction between LRRK2 and a-synuclein (Daher et al 2012). The deletion of LRRK2 did not influence the lethal neurodegenerative phenotype of PrP-A53T asynuclein transgenic mice, including premature survival, behavioral deficits, asynuclein pathology and gliosis, suggesting that a-synuclein-mediated neurodegeneration in hindbrain neurons occurs largely independent of LRRK2 expression in mice (Daher et al 2012). Although LRRK2 may selectively contribute to cellular aspects of a-synuclein-induced neuropathology, it is not yet clear whether inhibition of LRRK2 could be employed as a therapeutic strategy to attenuate asynuclein-mediated neuronal damage relevant to PD.…”