Clinical and Pathological Characteristics of Patients with Leucine-Rich Repeat Kinase-2 Mutations

Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6084, USA.
Movement Disorders (Impact Factor: 5.68). 01/2009; 24(1):32-9. DOI: 10.1002/mds.22096
Source: PubMed


Mutations in LRRK2 are the single most common known cause of Parkinson's disease (PD). Two new PD patients with LRRK2 mutation were identified from a cohort with extensive postmortem assessment. One of these patients harbors the R793M mutation and presented with the typical clinical and pathological features of PD. A novel L1165P mutation was identified in a second patient. This patient had the classical and pathological features of PD, but additionally developed severe neuropsychological symptoms and dementia associated with abundant neurofibrillary tangles in the hippocampal formation; features consistent with a secondary diagnosis of tangle-predominant dementia. alpha-Synuclein-containing pathological inclusions in these patients also were highly phosphorylated at Ser-129, similar to other patients with idiopathic PD. These two PD patients also were characterized by the presence of occasional cytoplasmic TDP-43 inclusions in the temporal cortex, a finding that was not observed in three other patients with the G2019S mutation in LRRK2. These findings extend the clinical and pathological features that may be associated with LRRK2 mutations.

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    • "The functions of LRRK2 are still largely unknown (reviewed in [6]), but aberrations in its kinase activity are thought to lead to pathogenesis [3, 9, 21, 31, 33, 67, 74]. Affected carriers of LRRK2 mutations are generally clinically indistinguishable from individuals with idiopathic PD and primarily present with Lewy body pathology [3, 19, 26, 61], but neuropathology is pleomorphic and often includes hyperphosphorylated tau protein inclusions [10, 17, 18, 43, 55, 58, 61, 71, 75]. "
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    ABSTRACT: Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson’s disease (PD). The neuropathology of LRRK2-related PD is heterogeneous and can include aberrant tau phosphorylation or neurofibrillary tau pathology. Recently, LRRK2 has been shown to phosphorylate tau in vitro; however, the major epitopes phosphorylated by LRRK2 and the physiological or pathogenic consequences of these modifications in vivo are unknown. Using mass spectrometry, we identified multiple sites on recombinant tau that are phosphorylated by LRRK2 in vitro, including pT149 and pT153, which are phospho-epitopes that to date have been largely unexplored. Importantly, we demonstrate that expression of transgenic LRRK2 in a mouse model of tauopathy increased the aggregation of insoluble tau and its phosphorylation at T149, T153, T205, and S199/S202/T205 epitopes. These findings indicate that tau can be a LRRK2 substrate and that this interaction can enhance salient features of human disease. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1188-4) contains supplementary material, which is available to authorized users.
    Full-text · Article · Oct 2013 · Acta Neuropathologica
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    • "To date, 51 disease-associated mutations in LRRK2 have been identified in familial or sporadic cases. These mutations are scattered throughout the entire LRRK2 gene, and include R1441C/G/H in the ROC domain, G2019S in the kinase domain, and G2385R in the WD40 domain [1]–[4]. Although there is evidence showing that expression of pathological LRRK2 mutations is sufficient to cause neurotoxicity in vitro [5], [6], transgenic LRRK2 mutant mice show little or no obvious degeneration of dopaminergic neurons [7]–[10]. "
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    ABSTRACT: LRRK2, a Parkinson's disease associated gene, is highly expressed in microglia in addition to neurons; however, its function in microglia has not been evaluated. Using Lrrk2 knockdown (Lrrk2-KD) murine microglia prepared by lentiviral-mediated transfer of Lrrk2-specific small inhibitory hairpin RNA (shRNA), we found that Lrrk2 deficiency attenuated lipopolysaccharide (LPS)-induced mRNA and/or protein expression of inducible nitric oxide synthase, TNF-α, IL-1β and IL-6. LPS-induced phosphorylation of p38 mitogen-activated protein kinase and stimulation of NF-κB-responsive luciferase reporter activity was also decreased in Lrrk2-KD cells. Interestingly, the decrease in NF-κB transcriptional activity measured by luciferase assays appeared to reflect increased binding of the inhibitory NF-κB homodimer, p50/p50, to DNA. In LPS-responsive HEK293T cells, overexpression of the human LRRK2 pathologic, kinase-active mutant G2019S increased basal and LPS-induced levels of phosphorylated p38 and JNK, whereas wild-type and other pathologic (R1441C and G2385R) or artificial kinase-dead (D1994A) LRRK2 mutants either enhanced or did not change basal and LPS-induced p38 and JNK phosphorylation levels. However, wild-type LRRK2 and all LRRK2 mutant variants equally enhanced NF-κB transcriptional activity. Taken together, these results suggest that LRRK2 is a positive regulator of inflammation in murine microglia, and LRRK2 mutations may alter the microenvironment of the brain to favor neuroinflammation.
    Full-text · Article · Apr 2012 · PLoS ONE
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    • "c o m / l o c a t e / b b a p a p domains have been formally confirmed to segregate with PD [8]. Variants in the LRR domain have also been reported (I1006M, R1067Q, S1096C, Q1111H, I1122V, L1165P, I1192V, S1228T & P1262A [9] [10] [11] [12] [13] [14] [15] [16] [17]), however because these variants are rare, a segregation with disease has not been confirmed. "
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    ABSTRACT: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease. Much research effort has been directed towards the catalytic core region of LRRK2 composed of GTPase (ROC, Ras of complex proteins) and kinase domains and a connecting COR (C-terminus of ROC) domain. In contrast, the precise functions of the protein-protein interaction domains, such as the leucine-rich repeat (LRR) domain, are not known. In the present study, we modeled the LRRK2 LRR domain (LRR(LRRK2)) using a template assembly approach, revealing the presence of 14 LRRs. Next, we focused on the expression and purification of LRR(LRRK2) in Escherichia coli. Buffer optimization revealed that the protein requires the presence of a zwitterionic detergent, namely Empigen BB, during solubilization and the subsequent purification and characterization steps. This indicates that the detergent captures the hydrophobic surface patches of LRR(LRRK2) thereby suppressing its aggregation. Circular dichroism (CD) spectroscopy measured 18% α-helices and 21% β-sheets, consistent with predictions from the homology model. Size exclusion chromatography (SEC) and dynamic light scattering measurements showed the presence of a single species, with a Stokes radius corresponding to the model dimensions of a protein monomer. Furthermore, no obvious LRR(LRRK2) multimerization was detected via cross-linking studies. Finally, the LRR(LRRK2) clinical mutations did not influence LRR(LRRK2) secondary, tertiary or quaternary structure as determined via SEC and CD spectroscopy. We therefore conclude that these mutations are likely to affect putative LRR(LRRK2) inter- and intramolecular interactions.
    Full-text · Article · Mar 2012 · Biochimica et Biophysica Acta
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