Similar to mammalian neurons, the expression of LRRK2-WT or LRRK2-G2019S did not adversely affect mitochondrial transport, whereas the LRRK2-R1441C or LRRK2-Y1699C mutants reduced the number of motile mitochondria in both anterograde and retrograde directions ( Fig. To investigate if this axonal transport defect occurred in vivo, we analysed the transport of mitochondria in motor neurons of Drosophila larvae expressing human LRRK2 variants. Thus, our data reveals a pathogenic mechanism and a potential therapeutic intervention for PD. Increasing microtubule acetylation prevents microtubule association, restores axonal transport and rescues locomotor deficits caused by LRRK2 Roc-COR mutants. Here we show that LRRK2 Roc-COR mutants disrupt axonal transport in vitro and in vivo to induce locomotor deficits by binding to deacetylated microtubules. Since defective axonal transport, which utilizes microtubules as transport tracks, has been proposed as a mechanism for PD 19, 20, 21, 22, 23, 24, we hypothesized that mutant LRRK2 may disturb microtubule-based axonal transport. The architecture of neurons makes them particularly dependent on efficient intracellular transport of cargoes such as organelles and proteins to maintain structural integrity and function.
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The molecular details underlying mutant LRRK2’s effects on neurites are not fully understood, but may involve interactions with microtubules 14, 15, 16, 17, 18. Indeed, there is evidence that the overexpression of LRRK2 causes neurite shortening, whereas the loss of LRRK2 function in mouse neurons results in elongation of neuronal processes and increased branching 10, 11, 12, 13. How LRRK2 mutations confer toxicity is not yet clear, but may involve the possible physiological function of LRRK2 in the maintenance of axonal integrity. Mutations in the Roc and COR domains decrease GTPase activity 6, 7, whereas the G2019S mutation increases kinase activity 6, 8, 9. LRRK2 is a multifunctional, multi-domain protein and dominant mutations have been identified in the Ras of complex (Roc) GTPase protein domain (R1441C, R1441G, R1441H), the carboxy-terminal of Roc (COR) domain (Y1699C) and the kinase domain (G2019S and I2020T). Thus, this study reveals a pathogenic mechanism and a potential intervention for Parkinson’s disease.ĭominant mutations in leucine-rich repeat kinase 2 ( LRRK2) are the most common genetic cause of Parkinson’s disease (PD), and genome-wide association studies have highlighted the LRRK2 locus as a risk factor for sporadic PD 1, 2, 3, 4, 5.
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In vivo knockdown of the deacetylases HDAC6 and Sirt2, or administration of TSA rescues both axonal transport and locomotor behavior. In vitro, increasing microtubule acetylation using deacetylase inhibitors or the tubulin acetylase αTAT1 prevents association of mutant LRRK2 with microtubules, and the deacetylase inhibitor trichostatin A (TSA) restores axonal transport. Here we find that LRRK2 containing pathogenic Roc-COR domain mutations (R1441C, Y1699C) preferentially associates with deacetylated microtubules, and inhibits axonal transport in primary neurons and in Drosophila, causing locomotor deficits in vivo.
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Defective microtubule-based axonal transport is hypothesized to contribute to Parkinson’s disease, but whether LRRK2 mutations affect this process to mediate pathogenesis is not known. LRRK2 is a multifunctional protein affecting many cellular processes and has been described to bind microtubules. Leucine-rich repeat kinase 2 ( LRRK2) mutations are the most common genetic cause of Parkinson’s disease.