Autosomal dominant Parkinsonism associated with variable synuclein and tau pathology
Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.Neurology (Impact Factor: 8.29). 06/2004; 62(9):1619-22. DOI: 10.1212/01.WNL.0000125015.06989.DB
Since the original 1995 report of a parkinsonian kindred, four individuals have been affected (mean age at onset, 65 years). All four had cardinal signs of Parkinson disease (PD) and good response to levodopa. Four autopsies showed neuronal loss and gliosis in the substantia nigra. Lewy bodies (LB) limited to brainstem nuclei were detected in one case, diffuse LB in the second, neurofibrillary tangles (NFT) without LB in the third, and neither NFT nor LB in the fourth. Genetic studies suggested linkage to the PARK8 locus on chromosome 12.
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- "Whether or not ubiquitin pathology contributes to neurite degeneration is not yet clear although ubiquitin-positive inclusions are not yet evident at 10 days following G2019S LRRK2 expression when there are already signs of neurite degeneration, perhaps suggesting that they occur as a consequence of neuronal damage. Notably, LRRK2-associated PD brains harboring the Y1699C mutation exhibit ubiquitin-positive inclusions as their sole protein pathology providing a precedent for the effects of G2019S LRRK2 in the rat striatum (Zimprich et al., 2004a; Wszolek et al., 2004). Ubiquitin-positive pathology and neurite degeneration in the striatum may provide useful and sensitive surrogate readouts of LRRK2 kinase activity for evaluating the efficacy of selective LRRK2 kinase inhibitors in future preclinical animal studies. "
ABSTRACT: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant Parkinson's disease (PD). LRRK2 contains functional GTPase and kinase domains. The most common G2019S mutation enhances the kinase activity of LRRK2 in vitro whereas G2019S LRRK2 expression in cultured neurons induces toxicity in a kinase-dependent manner. These observations suggest a potential role for kinase activity in LRRK2-associated PD. We have recently developed a novel rodent model of PD with progressive neurodegeneration induced by the adenoviral-mediated expression of G2019S LRRK2. In the present study, we further characterize this LRRK2 model and determine the contribution of kinase activity to LRRK2-mediated neurodegeneration. Recombinant human adenoviral vectors were employed to deliver human wild-type, G2019S or kinase-inactive G2019S/D1994N LRRK2 to the rat striatum. LRRK2-dependent pathology was assessed in the striatum, a region where LRRK2 protein is normally enriched in the mammalian brain. Human LRRK2 variants are robustly expressed throughout the rat striatum. Expression of G2019S LRRK2 selectively induces the accumulation of neuronal ubiquitin-positive inclusions accompanied by neurite degeneration and the altered distribution of axonal phosphorylated neurofilaments. Importantly, the introduction of a kinase-inactive mutation (G2019S/D1994N) completely ameliorates the pathological effects of G2019S LRRK2 in the striatum supporting a kinase activity-dependent mechanism for this PD-associated mutation. Collectively, our study further elucidates the pathological effects of the G2019S mutation in the mammalian brain and supports the development of kinase inhibitors as a potential therapeutic approach for treating LRRK2-associated PD. This adenoviral rodent model provides an important tool for elucidating the molecular basis of LRRK2-mediated neurodegeneration. Copyright © 2015. Published by Elsevier Inc.
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- "The kinase domain has the highest sequence homology to mitogen-activated protein kinase kinase kinase (MKKK)/MLKs (mixed lineage kinases) and receptor-interacting protein (RIP) kinase families. The most common mutation in LRRK2 associated with PD is the G2019S mutation located in the kinase domain of LRRK2 (Wszolek et al., 2004; Zimprich et al., 2004). Other common amino acid substitution include R1441C/G/H in the Roc GTPase domain and Y1699C in the COR domain (Taylor et al., 2006). "
ABSTRACT: LRRK2 is a protein that interacts with a plethora of signaling molecules, but the complexity of LRRK2 function presents a challenge for understanding the role of LRRK2 in the pathophysiology of Parkinson's disease (PD). Studies of LRRK2 using over-expression in transgenic mice have been disappointing, however, studies using invertebrate systems have yielded a much clearer picture, with clear effects of LRRK2 expression, knockdown or deletion in Caenorhabditis elegans and Drosophila on modulation of survival of dopaminergic neurons. Recent studies have begun to focus attention on particular signaling cascades that are a target of LRRK2 function. LRRK2 interacts with members of the mitogen activated protein kinase (MAPK) pathway and might regulate the pathway action by acting as a scaffold that directs the location of MAPK pathway activity, without strongly affecting the amount of MAPK pathway activity. Binding to GTPases, GTPase-activating proteins and GTPase exchange factors are another strong theme in LRRK2 biology, with LRRK2 binding to rac1, cdc42, rab5, rab7L1, endoA, RGS2, ArfGAP1, and ArhGEF7. All of these molecules appear to feed into a function output for LRRK2 that modulates cytoskeletal outgrowth and vesicular dynamics, including autophagy. These functions likely impact modulation of α-synuclein aggregation and associated toxicity eliciting the disease processes that we term PD.
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- "The functions of LRRK2 are still largely unknown (reviewed in ), 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]. "
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.
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