| Protein Name | Leucine-rich repeat kinase 2 (Dardarin) |
|---|---|
| Gene | LRRK2 |
| UniProt | Q5S007 |
| PDB Structures | 7L7E, 6HLE, 5W5V, 4D0D, 6OT0 |
| Molecular Weight | 286 kDa (2,527 aa) |
| Subcellular Localization | Cytoplasm, membrane-associated, nucleus |
| Protein Family | LRRK family, ROCO family |
| Expression | Brain (high in substantia nigra, cortex), kidney, lung |
LRRK2 (Leucine-Rich Repeat Kinase 2), also known as dardarin (from the Basque word "dardara" meaning "trembling"), is a large multi-domain protein kinase that is the most commonly mutated gene in familial Parkinson's disease (PD)[1]. LRRK2 is a 2,527-amino acid protein with both GTPase and kinase activities, making it a unique therapeutic target for PD intervention.
LRRK2 was identified as the causative gene for the PARK8 locus in 2004 and has since become one of the most intensively studied proteins in neurodegenerative disease research[2]. Pathogenic mutations in LRRK2 cause late-onset, clinically typical PD, making LRRK2 inhibitors a major focus of drug development efforts.
LRRK2 contains multiple functional domains arranged in a modular fashion[3]:
| Domain | Residues | Function |
|---|---|---|
| Armadillo repeats | 100-450 | Protein-protein interactions |
| Ankyrin repeats | 450-650 | Scaffold function |
| LRR domain | 650-950 | Leucine-rich repeats, substrate recognition |
| ROC domain | 950-1200 | GTPase activity (Ras of Complex proteins) |
| COR domain | 1200-1400 | Kinase regulation, dimerization |
| Kinase domain | 1400-1900 | Ser/Thr protein kinase |
| WD40 repeat | 1900-2527 | Protein interactions |
| Mutation | Domain | Effect | Prevalence |
|---|---|---|---|
| G2019S | Kinase | Increased kinase activity | ~5% familial PD, ~1% sporadic PD |
| R1441C/G/H | ROC | Impaired GTPase activity | ~3% familial PD |
| I2020T | Kinase | Increased activity | ~1% familial PD |
| N1437H | ROC | GTP binding defect | Rare |
| Y1699C | COR | Autoregulation | Rare |
Recent cryo-EM structures have revealed:
LRRK2 possesses two enzymatic functions:
Kinase Activity
GTPase Activity
LRRK2 mutations cause autosomal dominant Parkinson's disease[4]:
The G2019S mutation increases kinase activity by ~2-3 fold, leading to:
LRRK2 phosphorylates key PD-related proteins:
| Substrate | Site | Functional Consequence |
|---|---|---|
| Rab proteins | Various | Altered membrane trafficking |
| Tau | Multiple | Enhanced aggregation |
| α-Synuclein | Ser129 | Increased aggregation |
| 14-3-3 | Multiple | Loss of protective binding |
| Feature | LRRK2-PD | Idiopathic PD |
|---|---|---|
| Age of onset | 55-65 years | 60-70 years |
| Tremor | Less common | More common |
| Motor fluctuations | Similar | Similar |
| Dementia | Less common | More common |
| Neuropathology | Typical LB | Typical LB |
LRRK2 kinase inhibitors are in clinical development[5]:
| Drug | Company | Status | Notes |
|---|---|---|---|
| DNL151 | Denali | Phase 1b | CNS-penetrant |
| BIIB122 | Biogen/Denali | Phase 2 | Formerly DNL151 |
| GSK3357674A | GSK | Preclinical | Development paused |
| PF-06447475 | Pfizer | Phase 1 | Discontinued |
Targeting the ROC domain:
Paisán-Ruíz C, et al. (2004). Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron. 44(4):595-600. DOI:10.1016/j.neuron.2004.10.023
Zimprich A, et al. (2004). Mutations in LRRK2 cause familial Parkinson disease. Nat Genet. 36(9):999-1002. DOI:10.1038/ng1836
Cookson MR. (2010). The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nat Rev Neurosci. 11(12):791-797. DOI:10.1038/nrn2935
West AB, et al. (2005). Parkinson disease-associated mutations in LRRK2 link enhanced GTPase signaling to neurotoxicity. Hum Mol Genet. 14(1):103-114. DOI:10.1093/hmg/ddi012
Greggio E, et al. (2006). Kinase activity is required for the toxic effects of mutant LRRK2. J Neurosci. 26(47):11736-11742. DOI:10.1523/JNEUROSCI.4164-06.2006
Mata IF, et al. (2006). LRRK2 in Parkinson's disease: function and pathogenesis. Lancet Neurol. 5(6):513-522. DOI:10.1016/S1474-4422(06)70490-4
Albanese F, et al. (2023). LRRK2 kinase inhibition reduces LRRK2 pSer1292 in people with Parkinson's disease. Sci Transl Med. 15(692):eadh5315. DOI:10.1126/scitranslmed.adh5315
Taylor M, et al. (2021). LRRK2 and the autophagy-lysosome system in Parkinson's disease. Mol Neurodegener. 16(1):81. DOI:10.1186/s13024-021-00491-w
The study of Lrrk2 Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Paisán-Ruíz C, et al. (2004). Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron, 44(4):595-600. ↩︎
Zimprich A, et al. (2004). Mutations in LRRK2 cause familial Parkinson disease. Nat Genet, 36(9):999-1002. ↩︎
Cookson MR. (2010). The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nat Rev Neurosci, 11(12):791-797. ↩︎
Greggio E, et al. (2006). Kinase activity is required for the toxic effects of mutant LRRK2. J Neurosci, 26(47):11736-11742. ↩︎
Albanese F, et al. (2023). LRRK2 kinase inhibition reduces LRRK2 pSer1292 in people with Parkinson's disease. Sci Transl Med, 15(692):eadh5315. ↩︎