79 research outputs found

    Synthesis of two SAPAP3 isoforms from a single mRNA is mediated via alternative translational initiation

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    In mammalian neurons, targeting and translation of specific mRNAs in dendrites contribute to synaptic plasticity. After nuclear export, mRNAs designated for dendritic transport are generally assumed to be translationally dormant and activity of individual synapses may locally trigger their extrasomatic translation. We show that the long, GC-rich 5′-untranslated region of dendritic SAPAP3 mRNA restricts translation initiation via a mechanism that involves an upstream open reading frame (uORF). In addition, the uORF enables the use of an alternative translation start site, permitting synthesis of two SAPAP3 isoforms from a single mRNA. While both isoforms progressively accumulate at postsynaptic densities during early rat brain development, their levels relative to each other vary in different adult rat brain areas. Thus, alternative translation initiation events appear to regulate relative expression of distinct SAPAP3 isoforms in different brain regions, which may function to influence synaptic plasticity

    Student perceptions of veterinary anatomy practical classes: a longitudinal study

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    Using cadaveric material to teach veterinary students poses many challenges. However, little research exists on the contribution of this traditional approach to student learning. This longitudinal study aimed to investigate student perceptions of cadaver-based anatomy classes in a vertically integrated veterinary curriculum at the University of Nottingham's School of Veterinary Medicine and Science. Likert-scale statements and free-text boxes were used in a questionnaire distributed to second-year veterinary students (response rate 59%, 61/103). The same questionnaire was subsequently distributed to the same cohort 2 years later, in the students' fourth year of study (response rate 68%, 67/98). Students agreed that cadaver-based activities aid their learning, and they particularly value opportunities to develop practical skills while learning anatomy. There are few changes in perception as undergraduates progress to clinical years of teaching. Students perceive anatomy to be important, and feel that their learning has prepared them for clinical placements. This study emphasizes the importance of using cadaveric materials effectively in anatomy teaching and, in particular, using clinical skills training to enhance the anatomy curriculum

    Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation

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    Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Cytoplasmic fused in sarcoma (FUS) aggregates are pathological hallmarks of FUS-ALS. Proper shuttling between the nucleus and cytoplasm is essential for physiological cell function. However, the initial event in the pathophysiology of FUS-ALS remains enigmatic. Using human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs), we show that impairment of poly(ADP-ribose) polymerase (PARP)-dependent DNA damage response (DDR) signaling due to mutations in the FUS nuclear localization sequence (NLS) induces additional cytoplasmic FUS mislocalization which in turn results in neurodegeneration and FUS aggregate formation. Our work suggests that a key pathophysiologic event in ALS is upstream of aggregate formation. Targeting DDR signaling could lead to novel therapeutic routes for ameliorating ALS
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