Tong Y, Yamaguchi H, Giaime E, et al. Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of alpha-synuclein, and apoptotic cell death in aged mice. Proc Natl Acad Sci U S A. 2010;107:9879-84

Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2010; 107(21):9879-84. DOI: 10.1073/pnas.1004676107
Source: PubMed


Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. LRRK2 is a large protein containing a small GTPase domain and a kinase domain, but its physiological role is unknown. To identify the normal function of LRRK2 in vivo, we generated two independent lines of germ-line deletion mice. The dopaminergic system of LRRK2(-/-) mice appears normal, and numbers of dopaminergic neurons and levels of striatal dopamine are unchanged. However, LRRK2(-/-) kidneys, which suffer the greatest loss of LRRK compared with other organs, develop striking accumulation and aggregation of alpha-synuclein and ubiquitinated proteins at 20 months of age. The autophagy-lysosomal pathway is also impaired in the absence of LRRK2, as indicated by accumulation of lipofuscin granules as well as altered levels of LC3-II and p62. Furthermore, loss of LRRK2 dramatically increases apoptotic cell death, inflammatory responses, and oxidative damage. Collectively, our findings show that LRRK2 plays an essential and unexpected role in the regulation of protein homeostasis during aging, and suggest that LRRK2 mutations may cause Parkinson's disease and cell death via impairment of protein degradation pathways, leading to alpha-synuclein accumulation and aggregation over time.

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    • "Studies of LRRK2 using over-expression in transgenic mice have been disappointing, with few studies showing consistent effects occurring upon over-expression of wildtype or mutant LRRK2 (Dawson et al., 2010). Knockout of LRRK2 in the mouse yielded a strong phenotype in the kidney pointing to a role for LRRK2 in autophagy, however, no clear differences in the brain; this suggests that mammalian LRRK2 in vivo models do a better job of modeling cellular function/dysfunction rather than providing a more general model of PD (Tong et al., 2010). In contrast, over-expression studies using invertebrate systems have yielded much clearer results. "
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    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.
    Frontiers in Molecular Neuroscience 07/2014; 7:64. DOI:10.3389/fnmol.2014.00064 · 4.08 Impact Factor
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    • "Precise Ca 2+ imaging experiments in the context of both sporadic and familial PD models will be required to reveal possible alterations in intracellular Ca 2+ handling by these distinct organelles. For example, altered lysosomal Ca 2+ levels may be responsible for the observed changes in lysosomal morphology , clustering, and degradative capacity described for mutant LRRK2-expressing cells (MacLeod et al., 2006; Tong et al., 2010; Dodson et al., 2012; Gómez-Suaga et al., 2012; Orenstein et al., 2013). Such changes, concomitant with an increase in cytosolic Ca 2+ levels (Gómez-Suaga et al., 2012), may lead to aberrations in autophagic clearance, followed by a deficit in proteostasis. "
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    ABSTRACT: Parkinson's disease (PD) is a major health problem affecting millions of people worldwide. Recent studies provide compelling evidence that altered Ca(2) (+) homeostasis may underlie disease pathomechanism and be an inherent feature of all vulnerable neurons. The downstream effects of altered Ca(2) (+) handling in the distinct subcellular organelles for proper cellular function are beginning to be elucidated. Here, we summarize the evidence that vulnerable neurons may be exposed to homeostatic Ca(2) (+) stress which may determine their selective vulnerability, and suggest how abnormal Ca(2) (+) handling in the distinct intracellular compartments may compromise neuronal health in the context of aging, environmental, and genetic stress. Gaining a better understanding of the varied effects of Ca(2) (+) dyshomeostasis may allow novel combinatorial therapeutic strategies to slow PD progression.
    Frontiers in Molecular Neuroscience 06/2014; 7:53. DOI:10.3389/fnmol.2014.00053 · 4.08 Impact Factor
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    • "In addition , SNCA and protein carbonyls (a general marker of oxidative stress) levels also decrease whereas lysosomal proteins and proteases increase (Tong et al., 2012). However, neither autophagic nor lysosome-related structures accumulate in the brains of LRRK2 knockout mice, which suggests LRRK2 may have different roles in different tissues , or that in the absence of LRRK2, homologeus such as LRRK1 may compensate (Tong et al., 2010). Moreover the fact that LRRK2 expression levels in the central nervous system are decreased relatively to the renal tissue can signify that mutant LRRK2 or LRRK2 absence can cause subtle pathogenic effects throughout ageing which is in agreement with the late onset of the disease. "
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    ABSTRACT: Leucine-rich repeat kinase 2 (LRRK2) is a large, ubiquitous protein of unknown function. Mutations in the gene encoding LRRK2 have been linked to familial and sporadic Parkinson disease (PD) cases. The LRRK2 protein is a single polypeptide that displays GTPase and kinase activity. Kinase and GTPase domains are involved in different cellular signalling pathways. Despite several experimental studies associating LRRK2 protein with various intracellular membranes and vesicular structures such as endosomal/lysosomal compartments, the mitochondrial outer membrane, lipid rafts, microtubule-associated vesicles, the golgi complex, and the endoplasmic reticulum its broader physiologic function(s) remain unidentified. Additionally, the cellular distribution of LRRK2 may indicate its role in several different pathways, such as the ubiquitin-proteasome system, the autophagic-lysosomal pathway, intracellular trafficking, and mitochondrial dysfunction. This review discusses potential mechanisms through which LRRK2 may mediate neurodegeneration and cause PD.
    Experimental Neurology 06/2014; 261. DOI:10.1016/j.expneurol.2014.05.025 · 4.70 Impact Factor
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