Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). One of the most prominent gene targets of MeCP2 is brain-derived neurotrophic factor (Bdnf), a potent modulator of activity-dependent synaptic development, function and plasticity. Dysfunctional BDNF signaling has been demonstrated in several pathophysiological mechanisms of RTT disease progression. To evaluate whether the dynamics of BDNF trafficking is affected by Mecp2 deletion, we analyzed movements of BDNF tagged with yellow fluorescent protein (YFP) in cultured hippocampal neurons by time-lapse fluorescence imaging. We found that both anterograde and retrograde vesicular trafficking of BDNF-YFP are significantly impaired in Mecp2 knockout hippocampal neurons. Selective inhibitors of histone deacetylase 6 (HDAC6) show neuroprotective effects in neurodegenerative diseases and stimulate microtubule-dependent vesicular trafficking of BDNF-containing dense core vesicles. Here, we show that the selective HDAC6 inhibitor Tubastatin-A increased the velocity of BDNF-YFP vesicles in Mecp2 knockout neurons in both directions by increasing α–tubulin acetylation. Tubastatin-A also restored activity-dependent BDNF release from Mecp2 knockout neurons to levels comparable to those shown by wildtype neurons. These findings demonstrate that a selective HDAC6 inhibitor is a potential pharmacological strategy to reverse cellular and synaptic impairments in RTT resulting from impaired BDNF signaling.
Highlights
Rett syndrome (RTT), an X-linked postnatal neurodevelopmental disorder associated with intellectual disabilities, is primarily caused by mutations in methyl-CpG-binding protein 2 (MECP2), the gene encoding MeCP2, a transcriptional modulator that binds to methylated CpG sites in promoter regions of DNA (Nan et al, 1997; Amir et al, 1999; Percy and Lane, 2005)
To evaluate whether the dynamics of dendritic BDNF trafficking is altered by Mecp2 deletion, time-lapse fluorescence imaging of BDNF-yellow fluorescent protein (YFP) was performed in primary cultures of hippocampal neurons (12–14 days in vitro, DIV) from male Mecp2 knockouts and wildtype littermates
Since anterograde BDNF trafficking likely reflects delivery to release sites, while retrograde BDNF trafficking represents signaling endosomes directed to the cell nucleus (Egan et al, 2003; Park et al, 2008), our results suggest that both activitydependent BDNF release, as well as neurotrophin recycling and nuclear signaling are affected in MeCP2-deficient neurons
Summary
Rett syndrome (RTT), an X-linked postnatal neurodevelopmental disorder associated with intellectual disabilities, is primarily caused by mutations in methyl-CpG-binding protein 2 (MECP2), the gene encoding MeCP2, a transcriptional modulator that binds to methylated CpG sites in promoter regions of DNA (Nan et al, 1997; Amir et al, 1999; Percy and Lane, 2005). Conditional Bdnf mutant mice showed similar RTT phenotypes as Mecp knockout mice, while Bdnf overexpression rescued some of the functional deficits observed in Mecp mutants and extended their lifespan (Chang et al, 2006; Chahrour and Zoghbi, 2007). These findings strongly indicate BDNF plays a critical role in neurological dysfunctions in RTT
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