Chemical lesion models and older genetic models of PD that rely on aggressive phenotypes associated with mutant A53T h-synuclein expression may not be optimal to find the best LRRK2 kinase inhibitors. robust development pipeline seems possible and is needed to convincingly test the hypothesis that LRRK2 kinase inhibitors provide neuroprotection in PD. 2. Genetics of LRRK2-linked PD The importance of a target in disease pathogenesis and progression is often surmised through human genetics studies, changes to the target in post-mortem tissue, and action in model systems. Although PD is not a heritable condition in most people, there is a significant genetic component and is one of the major genes that underlies this type of risk(Lill et al., 2012; Trinh et al., 2014). With respect to PD susceptibility, genetic variants in can be assigned to three categories. First, mutations that are considered pathogenic (i.e., causative) have large effects on PD risk, for example, lifetime penetrance for PD of 20% or higher. For these large-effect mutations, segregation of patients with the mutations in multiple families proves the mutation is the causative factor. By far the most frequent mutation is the G2019S variant and is among the most prevalent known genetic causes of neurodegeneration(Trinh et al., 2014). Considerable effort has gone into understanding the functional effects of all the pathogenic mutations in as will be discussed. The second category of variants includes those associated with low-effect on PD risk, where the contribution is an order of magnitude or lower than pathogenic mutations. These variants include those identified in genome-wide association studies. It is difficult to determine whether these genetic variants are functional with respect to disease risk. They may act alone, or they may require synergy with other variants for effects, or they may be non-functional Bax inhibitor peptide V5 and in disequilibrium with other functional variants. Due to this relative increase in complexity compared to pathogenic mutations, relatively Bax inhibitor peptide V5 few studies have pursued these variants. The third category of genetic variants in PD includes those in PD cases but with no effect on PD susceptibility. This category includes the clear majority of variants in and involves tens of thousands of common and (mostly) rare coding and non-coding variants. At present, it appears that loss-of-function (LoF) variants (e.g., nonsense polymorphisms that block protein expression) can be included in this third category. In the ExAC Browser Beta database composed of 60,706 unrelated individuals, LoF variants are associated with a constraint metric score of null that indicates complete tolerance of loss of function mutations. Presently there is no clear consensus on how any of the second or third category variants may influence LRRK2 kinase activity in cells and tissues. 3. Genetic and biochemical support of a gain-of-function increase in LRRK2 kinase activity in PD susceptibility As LRRK2 is linked to PD susceptibility through genetics, understanding the functional impact of genetic variants that underlie PD risk will help identify the specific activities that should be prioritized for the development of new therapeutics. LRRK2 is part of an old family of proteins, known as the Ras-of-complex (Roc) family, with homologs in single-celled organisms that share as much as 30% amino-acid homology with LRRK2 in conserved domains like Roc and the COR domain Rabbit polyclonal to CD24 (Biotin) (C-terminal of Roc)(Bosgraaf and Van Haastert, 2003). LRRK2 contains several other domains found in hundreds of other proteins in humans, including the leucine-rich repeat (LRR), ankyrin repeat-like structures in the N-terminal domain, a protein kinase domain, and a WD40-like domain (Figure 1). These domains Bax inhibitor peptide V5 do not exist in a linear configuration but interact with one another in a complex regulatory cycle(Guaitoli et al., 2016; Liu et al., 2016). Not every Roc family protein contains a kinase domain, indicating that the kinase domain may be dispensable for some conserved functions, whereas the ~350 amino acid COR domain defines the family (Bosgraaf and Van Haastert, 2003). The Roc family (i.e., COR domain containing proteins) can be found in prokaryotes, amoeba, and plants, but no other kinases in humans apart from LRRK1 and LRRK2 contain a COR domain(Bosgraaf and Van Haastert, 2003). The first pathogenic mutation identified in with respect to LRRK2 kinase activity, pSer-1292 autophosphorylation(Sheng et al., 2012). The second substrate is in that includes phosphorylation of some Ras-family Rab GTPases(Steger et al., 2016). These.