Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice

Apoptosis, or programmed cell death, is a cellular pathway involved in normal cell turnover, developmental tissue remodeling, embryonic development, cellular homeostasis maintenance and chemical-induced cell death. Caspases are a family of intracellular proteases that play a key role in apoptosis. Aberrant activation of caspases has been implicated in human diseases. In particular, numerous findings implicate Caspase-6 (Casp6) in neurodegenerative diseases, including Alzheimer disease (AD) and Huntington disease (HD), highlighting the need for a deeper understanding of Casp6 biology and its role in brain development. The use of targeted caspase-deficient mice has been instrumental for studying the involvement of caspases in apoptosis. The goal of this study was to perform an in-depth neuroanatomical and behavioral characterization of constitutive Casp6-deficient (Casp6−/−) mice in order to understand the physiological function of Casp6 in brain development, structure and function. We demonstrate that Casp6−/− neurons are protected against excitotoxicity, nerve growth factor deprivation and myelin-induced axonal degeneration. Furthermore, Casp6-deficient mice show an age-dependent increase in cortical and striatal volume. In addition, these mice show a hypoactive phenotype and display learning deficits. The age-dependent behavioral and region-specific neuroanatomical changes observed in the Casp6−/− mice suggest that Casp6 deficiency has a more pronounced effect in brain regions that are involved in neurodegenerative diseases, such as the striatum in HD and the cortex in AD

Sketch map of the Songliao paleolake and Basin. Geochemistry of loess deposits in northeastern China: constraint on provenance and implication for disappearance of the large Songliao palaeolake

Supplementary Fig. 7 Sketch map of the Songliao paleolake and Basin, illustrating distribution and evolution of the large Songliao paleolake in the Quaternary (modified from Yang <i>et al.</i>, 1983; Sun, 1990; Qiu <i>et al.</i>, 2012)

Provenance discrimination diagrams used to identify whether mixed sources exist. Geochemistry of loess deposits in northeastern China: constraint on provenance and implication for disappearance of the large Songliao palaeolake

Supplementary Fig. 6 Provenance discrimination diagrams used to identify whether mixed sources exist. Trend lines on scattergrams are mass gain-mass loss paths extending from the origin. Note that the geochemical compositions for the Harbin aeolian loess locate between average compositions of the Horqin Sandy Land and the Songnen Sandy Land, indicating mixture of these two sandy lands

Prevention of depressive behaviour in the YAC128 mouse model of Huntington disease by mutation at residue 586 of huntingtin.

Huntington disease is a neurodegenerative disorder caused by an expanded CAG repeat in the Huntington disease gene. The symptomatic phase of the disease is defined by the onset of motor symptoms. However, psychiatric disturbances, including depression, are common features of Huntington disease and recent studies indicate that depression can occur long before the manifestation of motor symptoms. The aetiology of depression in Huntington disease is not fully understood and psychosocial factors such as the knowledge of carrying a mutation for an incurable disease or adverse social circumstances may contribute to its presentation. Due to the difficulties in discriminating between social and biological factors as contributors to depression in clinical Huntington disease, we chose to assess whether a model for Huntington disease not subject to environmental stressors, namely the YAC mouse model of Huntington disease, displays a depressive phenotype. Indeed, the YAC transgenic mice recapitulate the early depressive phenotype of Huntington disease as assessed by the Porsolt forced swim test as well as the sucrose intake test as a measure of anhedonia. The YAC model mirrors clinical Huntington disease in that there were no effects of CAG repeat length or disease duration on the depressive phenotype. The depressive phenotype was completely rescued in YAC transgenic animals expressing a variant of mutant huntingtin that is resistant to cleavage at amino acid 586 suggesting that therapies aimed towards inhibition of huntingtin cleavage are also likely to have beneficial effects on this aspect of the disease. In conclusion, our study provides strong support for a primary neurobiological basis for depression in Huntington disease

UCC-normalized patterns for major and trace elements of the Harbin loess and paleosols. Geochemistry of loess deposits in northeastern China: constraint on provenance and implication for disappearance of the large Songliao palaeolake

Supplementary Fig. 1 The UCC-normalized patterns for major and trace elements of the Harbin loess and paleosols, in comparison with the potential sources. UCC values are from Taylor and McLennan (1985)

Provenance discrimination diagrams integrating Nd isotopic composition with Th/Sc ratio and Eu anomaly. Geochemistry of loess deposits in northeastern China: constraint on provenance and implication for disappearance of the large Songliao palaeolake

Supplementary Fig. 5 Provenance discrimination diagrams integrating Nd isotopic composition with Th/Sc ratio and Eu anomaly, revealing a closer analogy to the Songnen Sandy Land and the Horqin Sandy Land for the Harbin aeolian loess sediments in comparison with the Hulun Buir Sandy Land

Provenance discrimination diagrams integrating immobile trace elements and REE for the Harbin loess and paleosols. Geochemistry of loess deposits in northeastern China: constraint on provenance and implication for disappearance of the large Songliao palaeolake

Supplementary Fig. 3: Provenance discrimination diagrams integrating immobile trace elements and REE for the Harbin loess and paleosols. Note that the Harbin dust samples fall within the field of the Songnen Sandy Land and the Horqin Sandy Land but far outside the field of the Hulun Buir Sandy Land, revealing a geochemical affinity of the Harbin aeolian loess with the the Songnen Sandy Land and Horqin Sandy Land

Concentrations (wt %) of major elements for the potential sources from which the Harbin aeolian loess is likely to be derived. Geochemistry of loess deposits in northeastern China: constraint on provenance and implication for disappearance of the large Songliao palaeolake

Supplementary table 1: Concentrations (wt %) of major elements for the potential sources from which the Harbin aeolian loess is likely to be derived