LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors

Hinkle, Kelly M.; Yue, Mei; Behrouz, Bahareh; Dächsel, Justus C.; Lincoln, Sarah; Bowles, Erin E.; Beevers, Joel E.; Dugger, Brittany N.; Winner, Beate; Prots, Iryna; Kent, Caroline; Nishioka, Kenya; Lin, Wen Lang; Dickson, Dennis W.; Janus, Christopher; Farrer, Matthew J.; Melrose, Heather L.

doi:10.1186/1750-1326-7-25

Cited by 170 publications

(175 citation statements)

References 62 publications

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“…Accumulating evidence indicates that LRRK2 is associated with membrane compartments [19,20] where it phosphorylates key proteins involved in membrane remodeling [17,21,22] and regulates different processes including autophagylysosome pathway [23], vesicular trafficking and protein sorting [14,24]. However, Lrrk2 -/-mice or rats show a normal dopaminergic system, with subtle or no alterations in the number of dopaminergic neurons and in the levels of striatal dopamine [25].…”

Section: Introductionmentioning

confidence: 99%

LRRK2 deficiency impacts ceramide metabolism in brain

Ferrazza

Cogo

Melrose

et al. 2016

Biochemical and Biophysical Research Communications

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Mutations in LRRK2 gene cause inherited Parkinson's disease (PD) and variations around LRRK2 act as risk factor for disease. Similar to sporadic disease, LRRK2-linked cases show late onset and, typically, the presence of proteinaceous inclusions named Lewy bodies (LBs) in neurons. Recently, defects on ceramide (Cer) metabolism have been recognized in PD. In particular, heterozygous mutations in the gene encoding for glucocerebrosidase (GBA1), a lysosomal enzyme converting glucosyl-ceramides (Glc-Cer) into Cer, increase the risk of developing PD. Although several studies have linked LRRK2 with membrane-related processes and autophagic-lysosomal pathway regulation, whether this protein impinges on the Cer pathway has not been addressed. Here, using a targeted lipidomics approach, we report an altered sphingolipid composition in Lrrk2 -/-mouse brains. In particular, we observe a significant increase of Cer levels in Lrrk2 -/-mice and direct effects on GBA1. Collectively, our results suggest a link between LRRK2 and Cer metabolism, providing new insights into the possible role of this protein in sphingolipids metabolism, with implications for PD therapeutics.

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Section: Introductionmentioning

confidence: 99%

LRRK2 deficiency impacts ceramide metabolism in brain

Ferrazza

Cogo

Melrose

et al. 2016

Biochemical and Biophysical Research Communications

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“…Adenovirus-mediated expression of the G2019S LRRK2 mutation in the nigrostriatal system of adult rats induces the accumulation of neuronal ubiquitin-positive inclusions and causes progressive degeneration of nigral DA neurons compared with wild-type rats [72, 73]. Similarly, symptoms of motor impairment, such as muscle weakness and dystonia, are evident in LRRK2 transgenic mice [74]. However, LRRK2 mutant animal models do not exhibit all the hallmarks of PD, such as Lewy bodies or DA neuron loss [75].…”

Section: Lrrk2 As a Therapeutic Targetmentioning

confidence: 99%

Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

Chen¹,

Chen²,

Pu³

2018

Eur Neurol

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Background: Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain. The pathogenesis of PD is not fully understood but is likely caused by a combination of genetic and environmental factors. Several genes are associated with the onset and progression of familial PD. There is increasing evidence that leucine-rich repeat kinase 2 (LRRK2) plays a significant role in PD pathophysiology. Summary: Many studies have been conducted to elucidate the functions of LRRK2 and identify effective LRRK2 inhibitors for PD treatment. In this review, we discuss the role of LRRK2 in PD and recent progress in the use of LRRK2 inhibitors as therapeutic agents. Key Messages: LRRK2 plays a significant role in the pathophysiology of PD, and pharmacological inhibition of LRRK2 has become one of the most promising potential therapies for PD. Further research is warranted to determine the functions of LRRK2 and expand the applications of LRRK2 inhibitors in PD treatment.

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“…LRRK2 knockout (KO) lines on mice were exon 41 deleted mice on a C57BL/6 background developed by Melrose and Farrer ((Hinkle et al, 2012); the Jackson Laboratory) with undetectable LRRK2 protein and no truncated LRRK2 products detected by immunoblot. LRRK2 KO rats on a Long-Evans Hooded outbred background were developed by Sigma Advanced Genetic Engineering Labs, via targeted genomic editing to introduce a 10 base pair deletion in exon 30 via Zinc-Finger Nuclease technology.…”

Section: Animalsmentioning

confidence: 99%

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

West

Cowell

Daher

et al. 2014

J of Comparative Neurology

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Mutations in leucine-rich repeat kinase 2 (LRRK2) are found in a significant proportion of lateonset Parkinson's disease (PD) patients. Elucidating the neuroanatomical localization of LRRK2 will further define LRRK2 function and the molecular basis of PD. Here, we utilize recently characterized monoclonal antibodies to evaluate LRRK2 expression in rodent brain regions relevant to PD. In both mice and rats, LRRK2 is highly expressed in the cortex and striatum, particularly in pyramidal neurons of layer V and in medium spiny neurons within striosomes. Overall, rats have a more restricted distribution of LRRK2 compared to mice. Mice, but not rats, show high levels of LRRK2 expression in the substantia nigra pars compacta. Expression of the pathogenic LRRK2-G2019S protein from mouse BAC constructs closely mimics endogenous LRRK2 distribution in the mouse brain. However, LRRK2-G2019S expression derived from human BAC constructs causes LRRK2 to be expressed in additional neuron subtypes in the rat such as striatal cholinergic interneurons and the substantia nigra pars compacta. The distribution of LRRK2 from human BAC constructs more closely resembles descriptions of LRRK2 in humans and non-human primates. Computational analyses of DNA regulatory elements in LRRK2 show a primate-specific promoter sequence that does not exist in lower mammalian species. These non-coding regions may be involved in directing neuronal expression patterns. Together, these studies will aid in understanding the normal function of LRRK2 in the brain and will assist in model selection for future studies.

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LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors

Cited by 170 publications

References 62 publications

LRRK2 deficiency impacts ceramide metabolism in brain

LRRK2 deficiency impacts ceramide metabolism in brain

Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

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

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