Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1711-0) contains supplementary material, which is available to authorized users.

The gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are produced in the embryonic pituitary in response to delivery of the hypothalamic gonadotropin releasing hormone (GnRH). GnRH has a pivotal role in reestablishing gonadotropin levels at puberty in primates, and for many species with extended reproductive cycles, these are reinitiated in response to central nervous system-induced GnRH release. Thus, a clear role is evident for GnRH in overcoming repression of these genes. Although the mechanisms through which GnRH actively stimulates LH and FSH ␤-subunit (FSH␤) gene transcription have been described in some detail, there is currently no information on how GnRH overcomes repression in order to terminate reproductively inactive stages. We show here that GnRH overcomes histone deacetylase (HDAC)-mediated repression of the gonadotropin ␤-subunit genes in immature gonadotropes. The repressive factors associated with each of these genes comprise distinct sets of HDACs and corepressors which allow for differentially regulated derepression of these two genes, produced in the same cell by the same regulatory hormone. We find that GnRH activation of calcium/calmodulin-dependent protein kinase I (CaMKI) plays a crucial role in the derepression of the FSH␤ gene involving phosphorylation of several class IIa HDACs associated with both the FSH␤ and Nur77 genes, and we propose a model for the mechanisms involved. In contrast, derepression of the LH ␤-subunit gene is not CaMK dependent. This demonstration of HDACmediated repression of these genes could explain the temporal shut-down of reproductive function at certain periods of the life cycle, which can easily be reversed by the actions of the hypothalamic regulatory hormone.In the mouse embryo, the pituitary gonadotropes become fully differentiated between embryonic day (E)11.5 when the common ␣-subunit is first expressed, and E16.5 when the luteinizing hormone ␤-subunit (LH␤) gene is first detected, while expression of the follicle-stimulating hormone ␤-subunit (FSH␤) gene appears on the following day. The expression of these genes is facilitated by unique cell-specific groups of transcription factors which are expressed in response to local signals, and most are present by E9 to 13.5 (6, 23, 50). Expression of these transcription factors (e.g., SF-1, Egr-1, and Pitx-1 for LH and SF-1, AP-1, Lhx3, Ptx1, and Ptx2 for FSH) has been shown to be sufficient to induce activity of the transiently transfected LH␤ and FSH␤ promoters in reporter gene assays in heterologous cells (9,20,27,41,55,56,61,67). However, LH␤ and FSH␤ gene expression in the developing gonadotrope appears only following the migration of the gonadotropin releasing hormone (GnRH) neurons in the hypothalamus and GnRH delivery to the pituitary, which starts around E16. This indicates a role for GnRH in initiating gonadotropin gene expression, which might be distinct from its stimulating increases in gonadotropin gene expression in mature gonadotropes, in which the gonadotropin genes ...

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The observation and manipulation of electron dynamics in matter call for attosecond light pulses, routinely available from high-order harmonic generation driven by few-femtosecond lasers. However, the energy limitation of these lasers supports only weak sources and correspondingly linear attosecond studies. Here we report on an optical parametric synthesizer designed for nonlinear attosecond optics and relativistic laser-plasma physics. This synthesizer uniquely combines ultra-relativistic focused intensities of about 10 20 W/cm 2 with a pulse duration of sub-two carrier-wave cycles. The coherent combination of two sequentially amplified and complementary spectral ranges yields sub-5-fs pulses with multi-TW peak power. The application of this source allows the generation of a broad spectral continuum at 100-eV photon energy in gases as well as high-order harmonics in relativistic plasmas. Unprecedented spatio-temporal confinement of light now permits the investigation of electric-fielddriven electron phenomena in the relativistic regime and ultimately the rise of next-generation intense isolated attosecond sources.The development and proliferation of intense lasers with sub-two optical-cycle duration during the past decade has allowed to create the tools and techniques for the observation and control of electronic motions in all forms of matter; a field nowadays known as attosecond physics 1 . These techniques have meanwhile provided direct time-domain access to a wide range of electron phenomena with a sub-fs resolution, such as miniscule delays in photo-emission timing 2,3 , charge migration in molecules 4, 5 and solids 6,7 , as well as collective electron motion in extreme laser-plasma interactions 8 . Powerful few-cycle laser pulses have traditionally been produced via chirped-pulse amplification (CPA) in titanium-doped sapphire (Ti:Sa) in conjunction with spectral broadening in gas-filled hollow-core fibres (HCF) 9 . CPA-based lasers have achieved peak powers beyond 1 PW, but only with pulse durations extending to about ten optical cycles or longer 10,11 . Spectral broadening in HCFs provides octave-spanning spectra, but the approach is still limited to pulses with a few millijoules in energy 12,13 . Due to these restrictions few-cycle-driven attosecond sources based on high-harmonic generation (HHG) in gas targets generally suffer from a low intensity, constituting a major limitation to pushing the frontiers of the field. Upscaling few-cycle-driven HHG to higher driving pulse energies [14][15][16] allows the generation of intense isolated attosecond pulses for time-resolved nonlinear optics experiments in the extreme-ultraviolet (XUV) spectral

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