Leucine-Rich Repeat Kinase 2 Gene-Associated Disease: Redefining Genotype-Phenotype Correlation

Abstract

Background: Leucine-rich repeat kinase 2 (LRRK2) has emerged as the most prevalent genetic cause of Parkinson’s disease (PD) among Caucasians. Patients carrying an LRRK2 mutation display significant variability of clinical and pathologic phenotypes across and within affected families. Methods: Herein, we review available clinical and pathologic data on patients with an LRRK2 mutation who have come to autopsy. Results: Thirty-eight patients have been reported who presented clinically with PD; parkinsonism with resistance to levodopa, supranuclear gaze palsy, or autonomic dysfunction; or tremor and dementia. Pathology showed typical PD-type Lewy body disease (LBD) in most patients, whereas in others there was ‘pure’ nigral degeneration (one with TDP-43-positive inclusions), diffuse LBD, or tau-, α-synuclein- or ubiquitin-positive pathology reminiscent of progressive supranuclear gaze palsy, multisystem atrophy, and frontotemporal dementia with ubiquitin-positive inclusions. Conclusions: Such clinical and pathologic variability suggests Lrrk2 acts upstream from other proteins implicated in neurodegeneration. Specific mutations may be associated with alternative progressive supranuclear gaze palsy-like or ‘pure’ nigral degeneration phenotypes. A different effect on Lrrk2 kinase activity may play a role in such heterogeneity.

(G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD

“…Double immunofluorescence staining also demonstrated a high level of (G2019S) LRRK2 expression in SNpc dopaminergic neurons of (G2019S) LRRK2 transgenic mouse. Consistent with previous studies showing a late-onset degeneration of SNpc dopaminergic neurons in (G2019S) LRRK2 PD patients, [11][12][13][14] 12-month-old (G2019S) LRRK2 transgenic mice prepared by us exhibited a significant neuronal death of SNpc dopaminergic cells, which progressively deteriorated in the following months. A reduction in striatal 99m Tc-TRODAT uptake of (G2019S) LRRK2 mice, visualized by microSPECT imaging, provided a direct in-vivo evidence of (G2019S) LRRK2-induced degeneration of nigrostriatal dopaminergic terminals.…”

“…6,7,10 Among LRRK2 mutations found in PD patients, G2019S is the most common amino-acid substitution. 6,7,10 PD patients with (G2019S) LRRK2 mutation displayed a loss of SNpc dopaminergic neurons, [11][12][13][14] indicating that (G2019S) LRRK2 causes neurodegeneration of SNpc dopaminergic cells and resulting in parkinsonism. A mouse model, which replicates (G2019S) LRRK2-induced degeneration of SNpc dopaminergic neurons, should be a valuable tool to investigate the pathogenic mechanism of (G2019S) LRRK2-induced PD.…”

“…26 Previous neuropathological examination reported the presence of a-synuclein-positive Lewy bodies in the brain of most (G2019S) LRRK2 PD patients. 11,12,14 However, SN neuronal loss in the absence of Lewy bodies was also found in some PD patients with (G2019S) LRRK2 mutation. 13,33 In the present study, we did not observe Lewy bodies or Lewy neurites in the SN of 12-to 16-month-old (G2019S) LRRK2 transgenic mice, which exhibit a significant neuronal death of SNpc dopaminergic cells.…”

“…[10][11][12] Neuropathological examination showed a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of PD patients with (G2019S) LRRK2 mutation. [11][12][13][14] Thus, mutant (G2019S) LRRK2 causes neurodegeneration of SNpc dopaminergic cells and resulting in parkinsonism.…”

Hypokinesia and Reduced Dopamine Levels in Zebrafish Lacking β- and γ1-Synucleins

“…We report here that zebrafish lack endogenous ␣-synuclein, which may cast doubt on whether key aspects of PD pathogenesis can be reproduced in a zebrafish model. ␣-Synuclein pathology is not prominent in some types of PD (62,63), and it is currently unclear whether ␣-synuclein is necessary for PD pathogenesis in all cases. However, we consider the construction of transgenic zebrafish lines expressing physiological levels of human or fish ␣-synucleins an important priority.…”