Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice

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: 9.81). 05/2010; 107(21):9879-84. DOI: 10.1073/pnas.1004676107
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Emilie Giaime, Jul 28, 2015
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 4.62 Impact Factor
  • Source
    • "The precise normal function of the leucine-rich repeat kinase 2 (LRRK2) has yet to be determined, although recent evidence suggests involvement in membrane trafficking (West et al., 2005; Biskup et al., 2006, 2007; Gloeckner et al., 2006; Hatano et al., 2007; Sakaguchi-Nakashima et al., 2007; Alegre-Abarrategui and Wade-Martins, 2009; Alegre-Abarrategui et al., 2009; Lee et al., 2010a,b,c; Tong et al., 2010; Vitte et al., 2010) and cytoskeletal dynamics (Jaleel et al., 2007; Gandhi et al., 2008; Gillardon, 2009; Parisiadou et al., 2009; Lin et al., 2010). Mutations in LRRK2 have been identified as the most common cause of dominantly inherited PD (Brice, 2005; Lesage et al., 2006; Ozelius et al., 2006; Healy et al., 2008) and importantly, variation in the LRRK2 gene has been implicated as a risk factor for sporadic PD (Kett and Dauer, 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized primarily by the selective death of dopaminergic (DA) neurons in the substantia nigra pars compacta of the midbrain. Although several genetic forms of PD have been identified, the precise molecular mechanisms underlying DA neuron loss in PD remain elusive. In recent years, microRNAs (miRNAs) have been recognized as potent post-transcriptional regulators of gene expression with fundamental roles in numerous biological processes. Although their role in PD pathogenesis is still a very active area of investigation, several seminal studies have contributed significantly to our understanding of the roles these small non-coding RNAs play in the disease process. Among these are studies which have demonstrated specific miRNAs that target and down-regulate the expression of PD-related genes as well as those demonstrating a reciprocal relationship in which PD-related genes act to regulate miRNA processing machinery. Concurrently, a wealth of knowledge has become available regarding the molecular mechanisms that unify the underlying etiology of genetic and sporadic PD pathogenesis, including dysregulated protein quality control by the ubiquitin-proteasome system and autophagy pathway, activation of programmed cell death, mitochondrial damage and aberrant DA neurodevelopment and maintenance. Following a discussion of the interactions between PD-related genes and miRNAs, this review highlights those studies which have elucidated the roles of these pathways in PD pathogenesis. We highlight the potential of miRNAs to serve a critical regulatory role in the implicated disease pathways, given their capacity to modulate the expression of entire families of related genes. Although few studies have directly linked miRNA regulation of these pathways to PD, a strong foundation for investigation has been laid and this area holds promise to reveal novel therapeutic targets for PD.
    Frontiers in Molecular Neuroscience 11/2013; 6:40. DOI:10.3389/fnmol.2013.00040
Show more