LRRK2
GeneName
LRRK2
Summary
LRRK2, also known as PARK8, hLRRK2, or LRRK-2, is a 286 kDa protein that functions as a multi-domain kinase and is predominantly expressed in the brain, particularly in neurons. It localises to various cellular compartments including the cytoplasm, mitochondria, endoplasmic reticulum, and lysosomes. LRRK2 is involved in numerous cellular processes such as autophagy, endocytosis, and synaptic transmission, and plays a role in the regulation of signalling pathways like the Wnt signalling pathway and MAPK cascade. Its kinase activity is crucial for various functions, including protein phosphorylation and GTPase activity, linking it to cellular responses to stressors like oxidative stress and dopamine.
Importance
LRRK2 is relevant to: - Parkinson’s disease, where mutations in the LRRK2 gene are the most common genetic cause, influencing neurodegeneration and synaptic function - Autophagy and protein degradation pathways, impacting cellular homeostasis and response to stress - Neuroinflammatory processes, given its role in microglial activation and neuronal health - Mitochondrial dynamics and function, as it is involved in mitochondrial localisation and organisation, which are critical for neuronal survival
Top Products
For researchers investigating LRRK2, we highly recommend the top-selling recombinant antibody, Anti-LRRK2 antibody [MJFF2 (c41-2)] (ab133474). This antibody has been validated in knockout models, ensuring its reliability in various applications, particularly in Western blotting (WB) and immunoprecipitation (IP). With 153 citations, it is well-regarded in the research community, making it a trusted choice for those studying LRRK2. Its recombinant nature guarantees batch-to-batch consistency, which is essential for reproducible results in your experiments. The Recombinant human LRRK2 protein ELISA Kit (ab177261) is a reliable option for researchers looking to measure LRRK2 levels in their samples.
Abcam Product Citation Summary
The data indicates a strong focus on the role of LRRK2 in various neurological contexts, particularly in relation to Parkinson's disease and neuroinflammatory responses. The use of Abcam antibodies in both human and mouse models highlights the relevance of LRRK2 in neuronal cell death, synaptic interactions, and cellular responses to injury. The studies encompass a range of applications, primarily Western blotting and immunohistochemistry, suggesting a comprehensive approach to understanding LRRK2's function and regulation in different biological systems.
Abcam Product Citation Table
Domain
The seven-bladed WD repeat region is critical for synaptic vesicle trafficking and mediates interaction with multiple vesicle-associated presynaptic proteins (PubMed:24687852). It also mediates homodimerization and regulates kinase activity (PubMed:30635421).
The COR domain mediates homodimerization; it also mediates homotetramerization via interaction with the protein kinase domain.
The Roc domain mediates homodimerization and regulates kinase activity.
Function
Serine/threonine-protein kinase which phosphorylates a broad range of proteins involved in multiple processes such as neuronal plasticity, innate immunity, autophagy, and vesicle trafficking (PubMed:17114044, PubMed:20949042, PubMed:21850687, PubMed:22012985, PubMed:23395371, PubMed:24687852, PubMed:25201882, PubMed:26014385, PubMed:26824392, PubMed:27830463, PubMed:28720718, PubMed:29125462, PubMed:29127255, PubMed:29212815, PubMed:30398148, PubMed:30635421). Is a key regulator of RAB GTPases by regulating the GTP/GDP exchange and interaction partners of RABs through phosphorylation (PubMed:26824392, PubMed:28720718, PubMed:29125462, PubMed:29127255, PubMed:29212815, PubMed:30398148, PubMed:30635421). Phosphorylates RAB3A, RAB3B, RAB3C, RAB3D, RAB5A, RAB5B, RAB5C, RAB8A, RAB8B, RAB10, RAB12, RAB29, RAB35, and RAB43 (PubMed:23395371, PubMed:26824392, PubMed:28720718, PubMed:29125462, PubMed:29127255, PubMed:29212815, PubMed:30398148, PubMed:30635421, PubMed:38127736). Regulates the RAB3IP-catalyzed GDP/GTP exchange for RAB8A through the phosphorylation of 'Thr-72' on RAB8A (PubMed:26824392). Inhibits the interaction between RAB8A and GDI1 and/or GDI2 by phosphorylating 'Thr-72' on RAB8A (PubMed:26824392). Regulates primary ciliogenesis through phosphorylation of RAB8A and RAB10, which promotes SHH signaling in the brain (PubMed:29125462, PubMed:30398148). Together with RAB29, plays a role in the retrograde trafficking pathway for recycling proteins, such as mannose-6-phosphate receptor (M6PR), between lysosomes and the Golgi apparatus in a retromer-dependent manner (PubMed:23395371). Regulates neuronal process morphology in the intact central nervous system (CNS) (PubMed:17114044). Plays a role in synaptic vesicle trafficking (PubMed:24687852). Plays an important role in recruiting SEC16A to endoplasmic reticulum exit sites (ERES) and in regulating ER to Golgi vesicle-mediated transport and ERES organization (PubMed:25201882). Positively regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway (PubMed:22012985). The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes (PubMed:22012985). Phosphorylates PRDX3 (PubMed:21850687). By phosphorylating APP on 'Thr-743', which promotes the production and the nuclear translocation of the APP intracellular domain (AICD), regulates dopaminergic neuron apoptosis (PubMed:28720718). Acts as a positive regulator of innate immunity by mediating phosphorylation of RIPK2 downstream of NOD1 and NOD2, thereby enhancing RIPK2 activation (PubMed:27830463). Independent of its kinase activity, inhibits the proteasomal degradation of MAPT, thus promoting MAPT oligomerization and secretion (PubMed:26014385). In addition, has GTPase activity via its Roc domain which regulates LRRK2 kinase activity (PubMed:18230735, PubMed:26824392, PubMed:28720718, PubMed:29125462, PubMed:29212815). Recruited by RAB29/RAB7L1 to overloaded lysosomes where it phosphorylates and stabilizes RAB8A and RAB10 which promote lysosomal content release and suppress lysosomal enlargement through the EHBP1 and EHBP1L1 effector proteins (PubMed:30209220, PubMed:38227290).
Involvement in disease
Parkinson disease 8
PARK8
A slowly progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, postural instability, neuronal loss in the substantia nigra, and the presence of neurofibrillary MAPT (tau)-positive and Lewy bodies in some patients.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Autophosphorylated at Ser-1292; autophosphorylation is stimulated by RAB29 (PubMed:28202711, PubMed:28720718, PubMed:29127255, PubMed:29212815, PubMed:30635421, PubMed:38127736). Phosphorylation of Ser-910 and either Ser-935 or Ser-1444 facilitates interaction with YWHAG (PubMed:28202711). Phosphorylation of Ser-910 and/or Ser-935 facilitates interaction with SFN (PubMed:28202711).
Ubiquitinated by TRIM1; undergoes 'Lys-48'-linked polyubiquitination leading to proteasomal degradation.
Sequence Similarities
Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.
Tissue Specificity
Expressed in pyramidal neurons in all cortical laminae of the visual cortex, in neurons of the substantia nigra pars compacta and caudate putamen (at protein level). Expressed in neutrophils (at protein level) (PubMed:29127255). Expressed in the brain. Expressed throughout the adult brain, but at a lower level than in heart and liver. Also expressed in placenta, lung, skeletal muscle, kidney and pancreas. In the brain, expressed in the cerebellum, cerebral cortex, medulla, spinal cord occipital pole, frontal lobe, temporal lobe and putamen. Expression is particularly high in brain dopaminoceptive areas.
Cellular localization
- Cytoplasmic vesicle
- Perikaryon
- Golgi apparatus membrane
- Peripheral membrane protein
- Cell projection
- Axon
- Cell projection
- Dendrite
- Endoplasmic reticulum membrane
- Peripheral membrane protein
- Cytoplasmic vesicle
- Secretory vesicle
- Synaptic vesicle membrane
- Endosome
- Lysosome
- Mitochondrion outer membrane
- Peripheral membrane protein
- Cytoplasm
- Cytoskeleton
- Cytoplasmic vesicle
- Phagosome
- Colocalized with RAB29 along tubular structures emerging from Golgi apparatus (PubMed:23395371, PubMed:38127736). Localizes to endoplasmic reticulum exit sites (ERES), also known as transitional endoplasmic reticulum (tER) (PubMed:25201882). Detected on phagosomes and stressed lysosomes but not detected on autophagosomes induced by starvation (By similarity). Recruitment to stressed lysosomes is dependent on the ATG8 conjugation system composed of ATG5, ATG12 and ATG16L1 and leads to lysosomal stress-induced activation of LRRK2 (By similarity).
Alternative names
PARK8, LRRK2, Leucine-rich repeat serine/threonine-protein kinase 2, Dardarin