This report describes Parkinson disease 8 (PARK8, PD8), which is a subtype of Parkinson disease; PARK8 exhibits autosomal dominant inheritance. The human gene implicated in this disease is LRRK2, a large protein with a serine/threonine protein kinase domain and several other motifs. There is a single fly ortholog, Lrrk, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple different UAS constructs of the human Hsap\LRRK2 gene have been introduced into flies, including wild-type LRRK2 and genes carrying mutational lesions implicated in PARK8. Heterologous rescue (functional complementation) of some aspects of the phenotype of a Dmel\Lrrk null mutation has been demonstrated. Phenotypic assays using the human gene have allowed characterization of genetic interactions with candidate fly genes and transgenic human genes.
Variant(s) implicated in human disease tested (as transgenic human gene, LRRK2): the I1122V, R1441C, Y1699C, G2019S, I2020T, and G2385R variant forms of the human gene have been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): R1069G in the fly Lrrk gene (corresponds to R1441G in the human LRRK2 gene), Y1383C in the fly Lrrk gene (corresponds to Y1699C in the human LRRK2 gene), G1914S in the fly Lrrk gene (corresponds to G2019S in the human LRRK2 gene), I1915T in the fly Lrrk gene (corresponds to I2020T in the human LRRK2 gene).
Loss-of-function mutations in the Dmel\Lrrk gene are viable; females are sterile or semi-sterile; observed phenotypes include aspects similar to Parkinson disease, such as locomotor behavior defective and neuroanatomy defective. Physical interactions of the Dmel\Lrrk protein product have been described; see below and in the Lrrk gene report. Phenotypic assays using the fly gene have allowed characterization of genetic interactions.
Therapeutic drug candidates and classes of deleterious compounds have been administered by feeding and tested using several different phenotypic assays.
[updated Dec. 2016 by FlyBase; FBrf0222196]
Parkinson disease (PD) is a neurodegenerative disease usually typified by slow onset in mid to late adulthood; there are also early-onset and juvenile forms of the disease. Symptoms worsen over time and include resting tremor, muscular rigidity, bradykinesia [abnormal slowness of movement], and postural instability [impaired balance and coordination]; additional symptoms may include postural abnormalities, dysautonomia [symptoms caused by malfunction of the autonomic nervous system], dystonic cramps, and dementia. Parkinson disease is the second-most common neurodegenerative disease (after Alzheimer disease), affecting approximately 1% of the population over 50 (Polymeropoulos et al., 1996, pubmed:8895469). [from MIM:168600; 2013.07.23]
Parkinson disease is described as early-onset disease if signs and symptoms begin before age 50. Early-onset cases that begin before age 20 may be referred to as juvenile-onset disease. [from Genetics Home Reference, GHR_condition:parkinson-disease, 2015.02.13]
[PARKINSON DISEASE 8, AUTOSOMAL DOMINANT; PARK8](https://omim.org/entry/607060)
[LEUCINE-RICH REPEAT KINASE 2; LRRK2](https://omim.org/entry/609007)
Parkinson disease 8 is characterized by typical symptoms of Parkinson disease (described above). It is one of the most common inherited forms of Parkinson disease. [from MIM:607060 and MIM:609007; 2015.02.16]
In humans, there is a second highly homologous gene, LRRK1, that lacks the N-terminal ankyrin repeat region; LRRK1 has not been found to be associated with Parkinson disease.
Parkinson disease 8 is described in terms of susceptibility, rather than as causative, because it exhibits variable and incomplete penetrance. The most severe variant, G2019S, results in a 20-fold increase in disease risk. In family-based studies, disease penetrance in LRRK2 p.G2019S carriers has been shown to be age dependent, increasing from about 20% at age 50 years to 80% at age 70 years. Other variants exhibit lower levels of penetrance; some may only double the risk of developing the disease (Dachsel and Farrere, 2010; pubmed:20457952).
Parkinson disease 8 exhibits an autosomal dominant pattern of transmission; shown to be caused by mutation(s) in the LRRK2 gene. One of the most commonly found mutations is G2019S (first described by Kachergus, et al., 2005, pubmed:15726496). Some patients with mutations in the LRRK2 gene may be classified as having Lewy body disease or Lewy body dementia (MIM:127750) or various forms of frontotemporal dementia (FTD; MIM:600274). [from MIM:607060 and MIM:609007; 2015.02.16]
Neuropathologic examinations show degeneration of the substantia nigra; Lewy bodies may or may not be present. [from MIM:607060; 2015.02.16]
LRRK2 undergoes autophosphorylation in vivo; Ser2032 and Thr2035 appear to be sites important for regulation of LRRK2 kinase activity (Li, et al., 2010, PMID: 20595391). T2035 is conserved in the D. melanogaster protein (human to fly isoform Lrrk-PB, T2035=T1930).
LRRK2 protein is large and complex, with a central kinase domain and several other motifs, including a Ras of complex (Roc) GTPase domain, a C-terminal of Roc (COR) domain, a leucine-rich repeat, an ankyrin repeat region, and a WD40 domain. The most prevalent PD-related LRRK2 amino acid substitution, G2019S, falls within the kinase domain. However, the kinase domain is not the only pathogenic target: mapped pathogenic mutations in familial PD8 fall into most of the multiple enzymatic and protein-interaction domains. (See Mata, et al., 2006, for a schematic of LRRK2 domain structure with positions of described mutations.)
LRRK2 is a large protein with a central kinase domain and several other motifs, including a Ras of complex (Roc) GTPase domain, a C-terminal of Roc (COR) domain, a leucine-rich repeat, an ankyrin repeat region, and a WD40 domain. Many PD-related mutations in the LRRK2 gene have been mapped and are found to be distributed in almost all domains of the protein; those confirmed as segregating in characterized families are found in the kinase, Roc and COR domains. The most common mutant form, G2019S, is within the kinase domain and has been shown to have hyperkinase activity.
The endocytic membrane-trafficking pathway and disruption of synaptic vesicle endocytosis appear to play major roles in the risk of Parkinson disease. A substantial amount of genetic variation in PD and parkinsonism has been associated with vesicle trafficking via endosomal gene alterations. (Bandres-Ciga et al., 2019, pubmed:30675927; Nguyen et al., 2019, pubmed:30509690). Relevant genes include DNAJC6 (see FBhh0000594, FBhh0000593), SYNJ1 (see FBhh0000626), GAK (see FBhh0000593) and SH3GL2, which are linked to clathrin-coated vesicles, and VPS35 (see FBhh0000030) and DNAJC13 (see FBhh0001155), which participate in recycling components from the endosomes to the Golgi. In addition, LRRK2 (see FBhh0000011) and PLA2G6 (see FBhh0000243, FBhh0000232) have been shown to interact with genes involved in endocytic membrane trafficking.
LRRK2 is a member of the leucine-rich repeat kinase family. Pharmacologic inhibitors of LRRK2 kinase activity are protective in mouse models of LRRK2-induced neurodegeneration (Lee et al., 2010, pubmed:20729864). The LRRK2 gene encodes a large protein with 5 putative functional domains: an N-terminal leucine-rich repeat (LRR) domain, a Roc (Ras of complex protein) domain that shares sequence homology to the Ras-related GTPase superfamily, a COR (C-terminal of Roc) domain, a mitogen-activated protein kinase kinase kinase (MAPKKK) domain, and a C-terminal WD40 repeat domain (summary by Gandhi et al., 2008, pubmed:18214993). [from MIM:609007; 2015.02.16]
Many to one: 2 human to 1 Drosophila; the human genes are LRRK2 and LRRK1.
Moderate-scoring ortholog of human LRRK2 and LRRK1 (1 Drosophila to 2 human); Dmel\Lrrk shares 22-23% identity and 36-38% similarity with the human genes.
