Lrrk2 and α-synuclein are co-regulated in rodent striatum

Westerlund, Marie; Ran, Caroline; Borgkvist, Anders; Sterky, Fredrik; Lindqvist, Eva; Lundströmer, Karin; Pernold, Karin; Brené, Stefan; Kallunki, Pekka; Fisone, Gilberto; Olson, Lar̀s; Galter, Dagmar

doi:10.1016/j.mcn.2008.08.001

Cited by 35 publications

(31 citation statements)

References 41 publications

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“…Furthermore, a current study has shown lower levels of α-synuclein in leukocytes of patients with G2019S LRRK2 mutation (Pchelina et al, 2011) and that α-synuclein and LRRK2 may be expressed synergistically in rodents (Westerlund et al, 2008). In addition, our group has shown that α-synuclein pathology affected regions in iPD and G2019S PD express lower levels of LRRK2 transcript compared to controls, in the absence of an effect on global gene expression levels (Devine et al, 2011; Sharma et al, 2011).…”

Section: Introductionmentioning

confidence: 63%

Divergent α-synuclein solubility and aggregation properties in G2019S LRRK2 Parkinson's disease brains with Lewy Body pathology compared to idiopathic cases

Mamais¹,

Raja²,

Manzoni³

et al. 2013

Neurobiology of Disease

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Mutations in LRRK2 are the most common genetic cause of Parkinson's disease (PD). The most prevalent LRRK2 mutation is the G2019S coding change, located in the kinase domain of this complex multi-domain protein. The majority of G2019S autopsy cases feature typical Lewy Body pathology with a clinical phenotype almost indistinguishable from idiopathic PD (iPD). Here we have investigated the biochemical characteristics of α-synuclein in G2019S LRRK2 PD post-mortem material, in comparison to pathology-matched iPD. Immunohistochemistry with pS129 α-synuclein antibody showed that the medulla is heavily affected with pathology in G2019S PD whilst the basal ganglia (BG), limbic and frontal cortical regions demonstrated comparable pathology scores between G2019S PD and iPD. Significantly lower levels of the highly aggregated α-synuclein species in urea–SDS fractions were observed in G2019S cases compared to iPD in the BG and limbic cortex. Our data, albeit from a small number of cases, highlight a difference in the biochemical properties of aggregated α-synuclein in G2019S linked PD compared to iPD, despite a similar histopathological presentation. This divergence in solubility is most notable in the basal ganglia, a region that is affected preclinically and is damaged before overt dopaminergic cell death.

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Section: Introductionmentioning

confidence: 63%

Divergent α-synuclein solubility and aggregation properties in G2019S LRRK2 Parkinson's disease brains with Lewy Body pathology compared to idiopathic cases

Mamais¹,

Raja²,

Manzoni³

et al. 2013

Neurobiology of Disease

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“…LRRK2 protein is well documented to be found at highest levels in the striatum in mammals (Galter et al, 2006; Melrose et al, 2006; Taymans et al, 2006; Higashi et al, 2007a; Higashi et al, 2007b; Melrose et al, 2007; Westerlund et al, 2008a; Westerlund et al, 2008b; Mandemakers et al, 2012; Davies et al, 2013a; Giesert et al, 2013; West et al, 2014). Therefore we reasoned that the G2019S mutation might impact on the functional integrity of the nigro-striatal dopaminergic pathway.…”

Section: Resultsmentioning

confidence: 99%

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice

Yue

Hinkle

Davies

et al. 2015

Neurobiology of Disease

212

214

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Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson’s disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock in mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24 months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6 months, by 12 months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug- evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S mice, which are consistent with mitochondrial fission arrest. We anticipate the G2019S will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression.

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“…LRRK2-immunoreactivity is also associated with LB (Higashi et al, 2007;Zhu et al, 2006). The expression of α- syn and LRRK2 appears co-regulated in the mouse striatum (Westerlund et al, 2008). These early studies indicate a potential pathophysiological interplay between α- syn and LRRK2 .…”

Section: Discussionmentioning

confidence: 99%

Leucine-Rich Repeat Kinase 2 Regulates the Progression of Neuropathology Induced by Parkinson's-Disease-Related Mutant α-synuclein

Lin

Parisiadou

et al. 2009

Neuron

459

474

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Summary Mutations in α-synuclein and Leucine-rich repeat kinase 2 (LRRK2) are linked to autosomal dominant forms of Parkinson’s disease (PD). However, little is known about any potential pathophysiological interplay between these two PD-related genes. Here we show in transgenic mice that although over-expression of LRRK2 alone did not cause neurodegeneration, the presence of excess LRRK2 greatly accelerated the progression of neuropathological abnormalities developed in PD-related A53T α-synuclein transgenic mice. Moreover, we found that LRRK2 promoted the abnormal aggregation and somatic accumulation of α-synuclein in A53T mice, likely resulted from the impairment of microtubule dynamics, Golgi organization, and ubiquitin-proteasome pathway. Conversely, genetic ablation of LRRK2 preserved the Golgi structure, suppressed the aggregation and somatic accumulation of α-synuclein, and thereby delayed the progression of neuropathology in A53T mice. These findings demonstrate that over-expression of LRRK2 enhances α-synuclein-mediated cytotoxicity and suggest inhibition of LRRK2 expression as a potential therapeutic option for ameliorating α-synuclein-induced neurodegeneration.

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Lrrk2 and α-synuclein are co-regulated in rodent striatum

Cited by 35 publications

References 41 publications

Divergent α-synuclein solubility and aggregation properties in G2019S LRRK2 Parkinson's disease brains with Lewy Body pathology compared to idiopathic cases

Divergent α-synuclein solubility and aggregation properties in G2019S LRRK2 Parkinson's disease brains with Lewy Body pathology compared to idiopathic cases

Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice

Leucine-Rich Repeat Kinase 2 Regulates the Progression of Neuropathology Induced by Parkinson's-Disease-Related Mutant α-synuclein

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