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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
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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.

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Available from: Emilie Giaime, Jul 28, 2015
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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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    • "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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    • "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). "
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