LRRK2 and Parkinson Disease

Abstract

To review the molecular genetics and functional biology of leucine-rich repeat kinase 2 (LRRK2) in parkinsonism and to summarize the opportunities and challenges to develop interventions for Parkinson disease (PD) based on this genetic insight. Data Sources: Publications cited are focused on LRRK2 biology between 2004 and March 2009. Study Selection: Literature selected was based on original contributions, seminal observations, and thoughtful reviews. Data Extraction: Unless stated otherwise, data was primarily abstracted from peer-reviewed literature appearing on PubMed. Data Synthesis: Genetic mutations that predispose PD are diagnostically useful in early or atypical presentations. The molecular pathways identified suggest therapeutic interventions for Lrrk2 and idiopathic PD and the rationale and opportunity to develop physiologically relevant biomarkers and experimental models with which to test them. Conclusions: Both affected and asymptomatic LRRK2 carriers now provide the opportunity to define the natural history of PD. This includes the frequency, penetrance, and rate of motor symptoms, nonmotor comorbidities, and their associated biomarkers.

Leucine-Rich Repeat Kinase 2 (Lrrk2) Deficiency Diminishes the Development of Experimental Autoimmune Uveitis (EAU) and the Adaptive Immune Response

“…This observation is in contrast to that of Liu et al [1], who found that Lrrk2 (-/-) mice developed more severe experimental colitis than their WT controls. The Lrrk2 (-/-) mice in the two studies were of the same colony, and the remarkable difference in their susceptibility to the two diseases could be mainly attributed to differences in the pathogenic mechanisms that mediate these two experimental diseases.…”

“…EAU is induced in mice by immunization with the retinal protein, interphotoreceptor retinoid-binding protein (IRBP). Unlike the observation with experimental colitis [1], mice deficient in Lrrk2 were found in our study to be less susceptible than the WT controls to the induction of EAU. In addition, the Lrrk2 (-/-) mice developed lower levels of cellular immunity against the immunizing antigen as compared to their WT controls.…”

Leucine-Rich Repeat Kinase 2 (Lrrk2) Deficiency Diminishes the Development of Experimental Autoimmune Uveitis (EAU) and the Adaptive Immune Response

“…This observation is in contrast to that of Liu et al [1], who found that Lrrk2 (-/-) mice developed more severe experimental colitis than their WT controls. The Lrrk2 (-/-) mice in the two studies were of the same colony, and the remarkable difference in their susceptibility to the two diseases could be mainly attributed to differences in the pathogenic mechanisms that mediate these two experimental diseases.…”

“…EAU is induced in mice by immunization with the retinal protein, interphotoreceptor retinoid-binding protein (IRBP). Unlike the observation with experimental colitis [1], mice deficient in Lrrk2 were found in our study to be less susceptible than the WT controls to the induction of EAU. In addition, the Lrrk2 (-/-) mice developed lower levels of cellular immunity against the immunizing antigen as compared to their WT controls.…”

Longitudinal Monitoring of Parkinson's Disease in Different Ethnic Cohorts: The DodoNA and LONG-PD Study

“…This may be explained by the different cohort sizes, but it may also reflect different genetic, environmental, and cultural factors. The prevalence of LRRK2 disease causing variants in sporadic PD has been reported between 0.5 and 2% ( 20 , 21 ) and that of GBA between 2.3 and 9.4% ( 22 ) in the U.S. population, similar to what we find in our cohort. It seems unlikely that the low percentage of LRRK2 and GBA disease-causing variants drives trajectory classification as there is a lack of contribution of family history to trajectory classification.…”

Rare copy number variants are an important cause of epileptic encephalopathies

“…SLCT1 acts as a linker protein between the voltage‐gated sodium channel Na v 1.8 and clathrin 55. LRRK2 is a brain‐expressed serine/threonine protein kinase in which gain‐of‐function mutations cause autosomal dominant early‐onset Parkinson disease 56. We hypothesized that complete loss of function of LRRK2 might lead to the MPSI phenotype in our patient, but we were unable to detect a mutation in the nondeleted allele (see Table 3).…”

Leucine-Rich Repeat Kinase 2 (Lrrk2) Deficiency Diminishes the Development of Experimental Autoimmune Uveitis (EAU) and the Adaptive Immune Response

“…This observation is in contrast to that of Liu et al [1], who found that Lrrk2 (-/-) mice developed more severe experimental colitis than their WT controls. The Lrrk2 (-/-) mice in the two studies were of the same colony, and the remarkable difference in their susceptibility to the two diseases could be mainly attributed to differences in the pathogenic mechanisms that mediate these two experimental diseases.…”

“…EAU is induced in mice by immunization with the retinal protein, interphotoreceptor retinoid-binding protein (IRBP). Unlike the observation with experimental colitis [1], mice deficient in Lrrk2 were found in our study to be less susceptible than the WT controls to the induction of EAU. In addition, the Lrrk2 (-/-) mice developed lower levels of cellular immunity against the immunizing antigen as compared to their WT controls.…”

Longitudinal Monitoring of Parkinson's Disease in Different Ethnic Cohorts: The DodoNA and LONG-PD Study

“…This may be explained by the different cohort sizes, but it may also reflect different genetic, environmental, and cultural factors. The prevalence of LRRK2 disease causing variants in sporadic PD has been reported between 0.5 and 2% ( 20 , 21 ) and that of GBA between 2.3 and 9.4% ( 22 ) in the U.S. population, similar to what we find in our cohort. It seems unlikely that the low percentage of LRRK2 and GBA disease-causing variants drives trajectory classification as there is a lack of contribution of family history to trajectory classification.…”

Rare copy number variants are an important cause of epileptic encephalopathies

“…SLCT1 acts as a linker protein between the voltage‐gated sodium channel Na v 1.8 and clathrin 55. LRRK2 is a brain‐expressed serine/threonine protein kinase in which gain‐of‐function mutations cause autosomal dominant early‐onset Parkinson disease 56. We hypothesized that complete loss of function of LRRK2 might lead to the MPSI phenotype in our patient, but we were unable to detect a mutation in the nondeleted allele (see Table 3).…”

Leucine-Rich Repeat Kinase 2 (Lrrk2) Deficiency Diminishes the Development of Experimental Autoimmune Uveitis (EAU) and the Adaptive Immune Response

“…This observation is in contrast to that of Liu et al [1], who found that Lrrk2 (-/-) mice developed more severe experimental colitis than their WT controls. The Lrrk2 (-/-) mice in the two studies were of the same colony, and the remarkable difference in their susceptibility to the two diseases could be mainly attributed to differences in the pathogenic mechanisms that mediate these two experimental diseases.…”

“…EAU is induced in mice by immunization with the retinal protein, interphotoreceptor retinoid-binding protein (IRBP). Unlike the observation with experimental colitis [1], mice deficient in Lrrk2 were found in our study to be less susceptible than the WT controls to the induction of EAU. In addition, the Lrrk2 (-/-) mice developed lower levels of cellular immunity against the immunizing antigen as compared to their WT controls.…”

Longitudinal Monitoring of Parkinson's Disease in Different Ethnic Cohorts: The DodoNA and LONG-PD Study

“…This may be explained by the different cohort sizes, but it may also reflect different genetic, environmental, and cultural factors. The prevalence of LRRK2 disease causing variants in sporadic PD has been reported between 0.5 and 2% ( 20 , 21 ) and that of GBA between 2.3 and 9.4% ( 22 ) in the U.S. population, similar to what we find in our cohort. It seems unlikely that the low percentage of LRRK2 and GBA disease-causing variants drives trajectory classification as there is a lack of contribution of family history to trajectory classification.…”

Rare copy number variants are an important cause of epileptic encephalopathies

“…SLCT1 acts as a linker protein between the voltage‐gated sodium channel Na v 1.8 and clathrin 55. LRRK2 is a brain‐expressed serine/threonine protein kinase in which gain‐of‐function mutations cause autosomal dominant early‐onset Parkinson disease 56. We hypothesized that complete loss of function of LRRK2 might lead to the MPSI phenotype in our patient, but we were unable to detect a mutation in the nondeleted allele (see Table 3).…”