The synaptic function of LRRK2.
ABSTRACT Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most frequent genetic lesions so far found in familial as well as sporadic forms of PD (Parkinson's disease), a neurodegenerative disease characterized by the dysfunction and degeneration of dopaminergic and other neuronal types. The molecular and cellular mechanisms underlying LRRK2 action remain poorly defined. Synaptic dysfunction has been increasingly recognized as an early event in the pathogenesis of major neurological disorders. Using Drosophila as a model system, we have shown that LRRK2 controls synaptic morphogenesis. Loss of dLRRK (Drosophila LRRK2) results in synaptic overgrowth at the Drosophila neuromuscular junction synapse, whereas overexpression of wild-type dLRRK, hLRRK2 (human LRRK2) or the pathogenic hLRRK2-G2019S mutant has the opposite effect. Alteration of LRRK2 activity also affects synaptic transmission in a complex manner. LRRK2 exerts its effects on synaptic morphology by interacting with distinct downstream effectors at the pre- and post-synaptic compartments. At the postsynapse, LRRK2 functionally interacts with 4E-BP (eukaryotic initiation factor 4E-binding protein) and the microRNA machinery, both of which negatively regulate protein synthesis. At the presynapse, LRRK2 phosphorylates and negatively regulates the microtubule-binding protein Futsch and functionally interacts with the mitochondrial transport machinery. These results implicate compartment-specific synaptic dysfunction caused by altered protein synthesis, cytoskeletal dynamics and mitochondrial transport in LRRK2 pathogenesis and offer a new paradigm for understanding and ultimately treating LRRK2-related PD.
SourceAvailable from: Austen J Milnerwood[Show abstract] [Hide abstract]
ABSTRACT: Mutations in Leucine-Rich Repeat Kinase-2 (LRRK2) result in familial Parkinson's disease and the G2019S mutation alone accounts for up to 30% in some ethnicities. Despite this, the function of LRRK2 is largely undetermined although evidence suggests roles in phosphorylation, protein interactions, autophagy and endocytosis. Emerging reports link loss of LRRK2 to altered synaptic transmission, but the effects of the G2019S mutation upon synaptic release in mammalian neurons are unknown. To assess wild type and mutant LRRK2 in established neuronal networks, we conducted immunocytochemical, electrophysiological and biochemical characterization of >3 week old cortical cultures of LRRK2 knock-out, wild-type overexpressing and G2019S knock-in mice. Synaptic release and synapse numbers were grossly normal in LRRK2 knock-out cells, but discretely reduced glutamatergic activity and reduced synaptic protein levels were observed. Conversely, synapse density was modestly but significantly increased in wild-type LRRK2 overexpressing cultures although event frequency was not. In knock-in cultures, glutamate release was markedly elevated, in the absence of any change to synapse density, indicating that physiological levels of G2019S LRRK2 elevate probability of release. Several pre-synaptic regulatory proteins shown by others to interact with LRRK2 were expressed at normal levels in knock-in cultures; however, synapsin 1 phosphorylation was significantly reduced. Thus, perturbations to the pre-synaptic release machinery and elevated synaptic transmission are early neuronal effects of LRRK2 G2019S. Furthermore, the comparison of knock-in and overexpressing cultures suggests that one copy of the G2019S mutation has a more pronounced effect than an ~3-fold increase in LRRK2 protein. Mutant-induced increases in transmission may convey additional stressors to neuronal physiology that may eventually contribute to the pathogenesis of Parkinson's disease.Frontiers in Cellular Neuroscience 09/2014; 8:301. DOI:10.3389/fncel.2014.00301 · 4.18 Impact Factor
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ABSTRACT: Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by a loss of dopaminergic neurons in the substantia nigra, as well as in other brain areas. The currently available dopamine replacement therapy provides merely symptomatic benefit and is ineffective because habituation and side effects arise relatively quickly. Studying the genetic forms of PD in animal models provides novel insight that allows targeting of specific aspects of this heterogenic disease more specifically. Among others, two important cellular deficits are associated with PD; these deficits relate to (1) synaptic transmission and vesicle trafficking, and (2) mitochondrial function, relating respectively to the dominant and recessive mutations in PD-causing genes. With increased knowledge of PD, the possibility of identifying an efficient, long-lasting treatment is becoming more conceivable, but this can only be done with an increased knowledge of the specific affected cellular mechanisms. This review discusses how discoveries in animal models of PD have clarified the therapeutic potential of pathways disrupted in PD, with a specific focus on synaptic transmission, vesicle trafficking, and mitochondrial function.Annals of the New York Academy of Sciences 12/2014; 1338(1). DOI:10.1111/nyas.12577 · 4.31 Impact Factor
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ABSTRACT: Synaptic dysfunction has been identified as an early neuropathologic event in Parkinson’s disease. Synapses depend critically on the adhesion of neurons to one another, glial cells, and the extracellular matrix. Cell-cell and cell-matrix adhesions regulate the structure and function of synapses, in part, through interactions with structural elements such as actin and microtubule proteins. These proteins are critical not only for neuronal structure and polarity, but also for the synaptic vesicle cycle, including maintenance of and transfer between vesicle pools, exocytosis, and vesicle recycling. Pathway analyses of genome wide association studies (GWAS) in Parkinson’s disease have identified frequent single nucleotide polymorphisms (SNPs) in cell adhesion pathways, suggesting that dysfunction in cell adhesion may play a role in disease pathology. Based on these observations, it may be hypothesized that Parkinson’s disease is due to synaptic dysfunction caused by genetic variations in cell adhesion pathways that affect actin and/or microtubule-mediated events in the synaptic vesicle cycle. Furthermore, it is hypothesized that cells with pacemaker-like activity—a characteristic of neurons that degenerate in Parkinson’s disease—may depend more on actin for recruiting synaptic vesicles for release than do less active neurons, thereby enhancing their sensitivity to SNPs in cell adhesion pathways and explaining the selectivity of neurodegeneration. Cells may ultimately die due to detachment from the extracellular matrix. This hypothesis suggests that further exploration of cell adhesion pathways and their linkage to neurotransmitter release through cell structural proteins such as actin and microtubules may provide important insights into Parkinson’s disease.Medical Hypotheses 08/2014; DOI:10.1016/j.mehy.2014.04.029 · 1.15 Impact Factor