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  • A question arising from this work

    2018-10-20

    A question arising from this work is whether development sets the stage for the early pathophysiological abnormalities in HD and whether we can identify candidate pathways or genes that will restore neuronal homeostasis and protect striatal MSNs halting disease progression. We believe the black and red modules defined in our studies represent critical cellular pathways that are disrupted in early HD pathogenesis and that normalization will restore neuronal homeostasis and prevent neuronal degeneration. Our bioinformatics analysis revealed key signaling molecules in neurogenesis, striatal development, and axonal guidance for these modules. To test whether these pathways were altered in HD and represented therapeutic targets for HD, we focused on two signaling pathways: TGF-β and netrin. During development the striatum forms from the ventral telencephalon and is dependent upon BMP/TGF-β inhibition (Kuang et al., 2006) as well as netrin-1 signaling (Hamasaki et al., 2001). Our studies of TGF-β signaling in HD reveal that this signaling pathway is altered in HD. Both HD NSCs and HD knockin mouse brains express more TGF-β than wild-type controls. Furthermore, TGF-β1 is neuroprotective in our NSC models and can ameliorate some HD phenotypes including reducing caspase activity and improving respiratory capacity in HD NSCs. These results suggest a possible compensatory mechanism in which HD NSCs express higher levels of TGF-β in order to compensate for the negative effects caused by the HD mutation. Our findings show that netrin-1 levels and receptors were altered in HD NSCs. The addition of axonal guidance molecule was neuroprotective consistent with the neuroprotective role of netrin-1 after stroke (Liao et al., 2013). In addition to these two signaling pathways, our analysis also revealed that the top WikiPathway was BDNF signaling for the top 100 genes. This agrees with the strong correlation of expression changes of BDNF knockout mice with human HD Apremilast (Kuhn et al., 2007, Strand et al., 2007) and numerous studies showing that BDNF is neuroprotective in HD (Crane et al., 2014). All of these findings support the use of NSCs for studying HD in its developmental phases.
    Experimental Procedures
    Author Contributions
    Acknowledgments
    Introduction Parkinson’s disease (PD) is recognized by a variety of progressive motor symptoms, with the majority of PD patients also suffering from non-motor symptoms that can occur before motor symptoms appear and may be independent of dopamine neuron loss (Gaig et al., 2014; Pont-Sunyer et al., 2015; van der Heeden et al., 2014). Evidence of pathological changes in the dorsal root ganglia and the vagus, glossopharyngeal, and internal superior laryngeal peripheral nerves is rapidly accumulating (Mu et al., 2013a, 2013b). Lewy body pathology has also been observed in the dorsal vagus ganglion and parasympathetic nuclei, enteric nervous system, and cardiac and pelvic plexus (Wakabayashi and Takahashi, 1997; Orimo et al., 2008; Beach et al., 2010; Tysnes et al., 2010; Cersosimo and Benarroch, 2012). It remains to be determined whether peripheral neuron damage precipitates the development of non-motor symptoms in PD, but focused analysis on the peripheral nervous system may ultimately provide information leading to broad therapeutic intervention. Most cases of PD are sporadic, but familial mutations account for nearly 10% of patients with PD (Toulouse and Sullivan, 2008). Mutations in leucine-rich repeat kinase 2 (LRRK2) cause an autosomal dominant form of PD that is clinically indistinguishable from sporadic PD (Marras et al., 2011; Alcalay et al., 2013; Gatto et al., 2013; Trinh et al., 2014). LRRK2 is a multi-domain kinase that exists as a dimer under physiological conditions, and several studies have indicated that the G2019S mutation significantly increases kinase activity (West et al., 2005; Greggio et al., 2006; Jaleel et al., 2007; Luzón-Toro et al., 2007; Anand et al., 2009; Covy and Giasson, 2009). Although the underlying pathogenesis of PD remains poorly understood, increased LRRK2 kinase activity likely plays a key role in LRRK2-linked PD (Greggio et al., 2006; MacLeod et al., 2006; Smith et al., 2006; Lee et al., 2010; Deng et al., 2011).