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FLASH GENE
Symbol LRRK2 contributors: mct/shn - updated : 05-10-2018
HGNC name leucine-rich repeat kinase 2
HGNC id 18618
ASSOCIATED DISORDERS
corresponding disease(s) PARK8
Other morbid association(s)
TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
constitutional       gain of function
mutation Gly2019Ser enhances catalytic activity
tumoral     --over  
with MET protein kinases in papillary renal cell carcinoma and in papillary thyroid carcinoma
Susceptibility to sporadic Parkinson disease
Variant & Polymorphism SNP increasing the risk of sporadic Parkinson disease
Candidate gene
Marker
Therapy target
SystemTypeDisorderPubmed
neurologyneurodegenerativeParkinson/dementia Parkinsonism
may be a target for future therapeutic intervention in Parkinson disease
neurologyneurodegenerativeParkinson/dementia Parkinsonism
inhibition of LRRK2 expression is a potential therapeutic option for ameliorating alpha-synuclein-induced neurodegeneration
cancerurinary 
targeting LRRK2 may be an attractive pharmacologic strategy to complement MET inhibitors in patients with specific papillary tumors or to treat patients with germ-line LRRK2 mutations that predispose them to both Parkinson disease and epithelial cancers
ANIMAL & CELL MODELS
  • mutant LRRK2 causes neuronal degeneration in both SH-SY5Y cells and primary neurons
  • neurons expressing disease-associated mutant forms of LRRK2 display reduced neurite process length and complexity, tau-positive inclusions with lysosomal features, and ultimately apoptotic cell death
  • neurons deficient in LRRK2 harbor extended neuritic processes with increased branching
  • transgenic Drosophila expressing LRRK2-G2019S mutation display retinal degeneration, selective loss of dopaminergic neurons, locomotor dysfunction, more severe parkinsonism and early mortality
  • LRRK2 transgenic mouse model display an age-dependent and levodopa-responsive slowness of movement associated with diminished dopamine release and axonal pathology of nigrostriatal dopaminergic projection (
  • transgenic mice that although overexpression of LRRK2 alone did not cause neurodegeneration, the presence of excess LRRK2 greatly accelerated the progression of neuropathological abnormalities developed in PD-related A53T alpha-synuclein transgenic mice (
  • transgenic mouse strains overexpressing LRRK2 wild-type have elevated striatal dopamine (DA) release with unaltered DA uptake or tissue content, are hyperactive and show enhanced performance in motor function tests (
  • transgenic mouse strains overexpressing LRRK2 mutant G2019S display an age-dependent decrease in striatal dopamin content, as well as decreased striatal dopamin release and uptake (
  • dopaminergic system of LRRK2(-/-) mice appears normal, and numbers of dopaminergic neurons and levels of striatal dopamine are unchanged but LRRK2(-/-) kidneys develop striking accumulation and aggregation of alpha-synuclein and ubiquitinated proteins at 20 months of age. loss of LRRK2 dramatically increases apoptotic cell death, inflammatory responses, and oxidative damage (
  • abnormal dopamine neurotransmission in both hWT and G2019S transgenic LRRK2 mice evidenced by a decrease in extra-cellular dopamine levels (
  • Mice completely lacking the LRRK2 protein (KO) showed an early-onset marked increase in number and size of secondary lysosomes in kidney proximal tubule cells and lamellar bodies in lung type II cells
  • Mice expressing a LRRK2 kinase-dead mutant (KD) from the endogenous locus displayed similar early-onset pathophysiological changes in kidney but not lung and had had dramatically reduced full-length LRRK2 protein levels in the kidney
  • Knock-in (KI) mice expressing the G2019S PD-associated mutation that increases LRRK2 kinase activity showed none of the LRRK2 protein level and histopathological changes observed in KD and KO mice