- The LRRK2 protein is expressed predominantly in nervous tissue, the kidneys, the respiratory system and the immune system (monocytes, neutrophils, B cells), so LRRK2 kinase inhibition could lead to various peripheral effects.
- microglia do not express LRRK2, nor do T cells that infiltrate the brain. (https://www.natureasia.com/en/nmiddleeast/article/10.1038/nmiddleeast.2018.41)
Inflammation and LRRK2
- i) LRRK2 is highly expressed in microglia (Kunisada, Yuya)
- a. 당연히 Single cell analysis seq data in human brain hiPS-microglia
- b. LRRK2 might regulate TNFα production in microglia (Dong Hwan Ho, et al. Experimental Neurobiology (2018))
MOA
| In PD | LRRK2 missense mutation (G2019S mutation in activation loop of LRRK2) | ↑ phosphorylation of serine 935 (pS935) of LRRK2 (Autophosphorylation) (Padmanabhan, 2019 #788) | ↑ (x2-3) LRRK2 Kinase activity TE | ↑ phosphorylation of its substrates, Rab8 and Rab10 [6]. | ↑ Rab10 phosphorylation (→ GDP (guanosine diphosphate) dissociation inhibitor factors (necessary for membrane delivery & recycling) → ↓ Rab10 activity | 세포내 Rab의 위치(localization)가 바뀌면서 | Impairs vesicle trafficking | ↓ autophagy (how? Rab는 endosome에 작용인데?) | ↑ release of poorly digested aSyn aggregates into the extracellular space | aSyn spread | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Evidence: human | [DNL151 P1] After normalizing for total LRRK2 levels, pRab10 was elevated by ~2-fold in patients with sporadic Parkinson's disease and in LRRK2 mutation carriers compared with HV | release lysosomal proteases | Neuroinflammation | ||||||||
| Evidence: human iPS | (Rivero-Ríos, 2020 #1169)revew 에 여러 (p7)증거 열거 | (Sánchez-Danés, 2012 #1173) ↑ autophagosome number, LC3 I&II 이상, ↓ colocalization of LAMP1 and LC3, ↑ aSyn | |||||||||
| Evidence: in vivo | (Tolosa, 2020 #2036)2nd, All pathogenic mutations in LRRK2 that have been tested increase Rab phosphorylation in vivo75 | ||||||||||
| Evidence: mice |
(Rivero-Ríos, 2020 #1169) ↑ autophagosome number, but ↓ acidic lysosome number ↑ lysosomal pH, ↓ lysosomal protein degradation capacity, altered lysosomal calcium dynamics in cortical neurons from BAC transgenic rats expressing R1441C LRRK2 (Wallings et al., 2019). {Henry, 2015 #1174} [mice astrocyte] = (global) proteolysis, ↓ lsosomal degradation, ↓ cathepsin B activity, etc, Lysosomal enlargement, (protein accumulation은 안봄) |
Mitophagy and LRRK2
| (Singh, 2021 #1650) | ↓ Mitophagy in LRRk2 | ||||
Mutation
- h. Mutation → overexpression
- i. Over 100 LRRK2 distinct missense and non-sense mutations have been so far documented in PD families and sporadic cases,
- j. of which G2019S missense mutation is the most common (R1441 is the next),
- p.Gly2019Ser is within exon 41
- G2019S mutation, which is common in Whites, confers a higher risk for PD than the common Asian variants, G2385R and R1628P
- k. but only around one dozen are pathogenic
- l. several well-known pathogenic variants have been shown to increase phosphorylation of known LRRK2 substrates [Greggio & Cookson 2009, Sheng et al 2012, Steger et al 2016].
- m. JNC, 2014. 131: 554-565
- n. (Tolosa, 2020 #2036)
- o. (LRRK2 protein domain diagrams)
LRRK2 protein domain diagram (left, top labels above kinase region): R1441C/G/H, Y1699C, G2019S, I2020T
Domain boxes (left → right): ANK · LRR · Roc · COR · Kinase · WD40
Position markers below domains: 705 · 860 · 984 · 1278 · 1335 · 1510 · 1511 · 1878 · 1879 · 2138 · 2142 · 2498 · 25
LRRK2 protein domain diagram (right, full schematic with variant call-outs):
- Variant labels (top → above each domain region): Lys616Arg, Lys544Glu, Glu344Lys, Ala211Val, Pro755Leu, Ser973Asn, Gln923His, Arg1325Gln, Ile1371Val, Thr1410Met, Ser1508Arg, Ala1464Gly, Arg1441Gly, Arg1441Cys, Arg1441His, Asn1437His, Tyr1699Cys, Arg1514Gln, Arg1725Gln, Met1869Thr, Gln1823Lys, Ile1991Val, Ile2012Thr, Gly2019Ser, Ile2020Thr, Leu2439Ile, Thr2356Ile, Asp2175His
- Position markers: 1 · 62 · 650 · 690 · 860 · 984 · 1278 · 1335 · 1510 · 1878 · 2138 · 2498 · 2527
- Domain boxes (left → right): Armadillo repeat · Ankyrin repeat · Leucine-rich repeat · Roc domain · COR domain · Protein kinase · WD40 repeat
- Bottom group labels: Protein-protein interaction | GTPase | Kinase | Protein-protein interaction
LRRK2 Pathogenic Variants
| Reference Sequences | DNA Nucleotide Change | Predicted Protein Change | Comment [Reference] |
|---|---|---|---|
| 98578.4 10980.4 | c.4321C>T | p.Arg1441Cys | Founder variant in the Basque population & may be more common in southern Italian & Belgian populations - see Prevalence |
| c.4321C>G | p.Arg1441Gly | Associated with excessive tremor - see Genotype-Phenotype Correlations [Paisán-Ruíz et al 2004, Mata et al 2005b] | |
| c.4322G>A | p.Arg1441His | See Genotype-Phenotype Correlations. | |
| c.4321C>A | p.Arg1441Ser | ||
| c.6059T>C | p.Ile2020Thr | The change found in the original LRRK2 family [Funayama et al 2005] | |
| c.6055G>A | p.Gly2019Ser |
Most frequent pathogenic variant - see Genotype-Phenotype Correlations, Penetrance, and Prevalence [West et al 2005, Greggio et al 2006, MacLeod et al 2006, Smith et al 2006, Jaleel et al 2007]. ii) Homozygous p.Gly2019Ser cases are not phenotypically different from heterozygous cases [Ishihara et al 2006, Ben Romdhan et al 2018]. iii) {Iwaki, 2020 #2032} 833 p.G2019S heterozygote carriers (439 PD and 394 unaffected) were analyzed. Polygenic risk score was associated with a higher penetrance of PD (odds ratio: 1.34; 95% confidence interval: [1.09, 1.64] per + 1 standard deviation: P = 0.005) |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| LRRK2 left domain diagram trailing label “25” near the right end | 25 / 2498 | A small “25” label appears separately from the main 2498 marker; possibly part of “2527”; transcribed as seen. |
| Right domain diagram position 690 | 690 | 690 marker visible as a tick label between Armadillo-repeat and Ankyrin-repeat; partially small. |
| MOA ”↑ Rab10 activity” cell | ”→ ↓ Rab10 activity” | The arrow direction near the closing parenthesis is small; transcribed from visible glyphs. |
| MOA Evidence: in vivo footnote “in vivo75” | superscript 75 | Trailing superscript number after “in vivo” small and tight against the word; transcribed as 75. |