Predominant Spastic Paraparesis Associated With the D178N Mutation in PRNP

Here we report on a 70-year-old female presenting with an unusual progressive syndrome with fatal outcome. The predominant features in this case were spastic paraparesis, cognitive decline and respiratory failure. Relatives affected with a similar syndrome were previously diagnosed with lipofuscinosis. However, whole-genome sequencing (WGS) in our case did not reveal any pathogenic variants in genes associated with lipofuscinosis, but instead detected the known D178 variant in PRNP. The course of disease was rapid despite the presence of methione at codon 129 in the mutated and valine in the healthy allele of PRNP. Typical neuropathological abnormalities for familial fatal insomnia (FFI) were found, Western blot analysis suggested a type 2B prion protein isoform. The serendipitous diagnosis obtained with WGS illustrates a role for the method in elusive cases

The Role of BDNF in Experimental and Clinical Traumatic Brain Injury

Traumatic brain injury is one of the leading causes of mortality and morbidity in the world with no current pharmacological treatment. The role of BDNF in neural repair and regeneration is well established and has also been the focus of TBI research. Here, we review experimental animal models assessing BDNF expression following injury as well as clinical studies in humans including the role of BDNF polymorphism in TBI. There is a large heterogeneity in experimental setups and hence the results with different regional and temporal changes in BDNF expression. Several studies have also assessed different interventions to affect the BDNF expression following injury. Clinical studies highlight the importance of BDNF polymorphism in the outcome and indicate a protective role of BDNF polymorphism following injury. Considering the possibility of affecting the BDNF pathway with available substances, we discuss future studies using transgenic mice as well as iPSC in order to understand the underlying mechanism of BDNF polymorphism in TBI and develop a possible pharmacological treatment

No difference in microglia activation as measured by Iba1 IR between WT, C3^−/− and K^b−/−D^b−/− mice one week after sciatic nerve lesion.

<p>Immunoreactivity for Iba1 was measured in the sciatic motoneuron pool in WT (first row), C3^−/− (second row) and K^b−/−D^b−/− mice (third row). Ipsilateral (IL, second column) to contralateral (CL, first column) ratio of semiquantative measurements was quantified in the third column. In WT mice, Iba1 IR IL/CL ratio was increased to 5.22 and 5.21 of the value on the control side in the two studied sets of experiment. In C3^−/− mice the corresponding increase in IL/CL ratio was 5.05, and in K^b−/−D^b−/−5.39. Insets indicate 50× magnification micrographs of Iba1 IR around individual motoneurons. Six animals were studied in each group. Error bars indicate SEM, unpaired t-test. Scale bar = 50 µm.</p

Reduced synaptic stripping in <i>C3^−/−</i> mice and augmented stripping in K^b−/−D^b−/− mice compared to WT control one week after sciatic nerve lesion.

<p>Immunoreactivity (IR) for synaptophysin in the sciatic motoneuron pool of WT mice (A). Control staining with primary antibody omitted and replaced by non-immunized rabbit serum (B). Ipsilateral (IL) to contralateral (CL) ratio of semiquantative measurements of synaptophysin IR was quantified for WT (C), <i>C3^−/−</i> (D) and K^b−/−D^b−/− (E). For WT unlesioned mice the IL/CL ratio was 1.04±0.07 compared to 0.71±0.05 for the lesioned mice (C). For <i>C3^−/−</i> mice synaptophysin IR IL/CL ratio was decreased to 0.92 and for WT to 0.68 (D) and for K^b−/−D^b−/− IL/CL ratio to 0.55 and for WT 0.74 (E). Six animals were used in each group. Error bars indicate SEM, * = p<0.05, unpaired t-test. Scale bar = 50 µm.</p

Mir-17∼92 Governs Motor Neuron Subtype Survival by Mediating Nuclear PTEN

Motor neurons (MNs) are unique because they project their axons outside of the CNS to innervate the peripheral muscles. Limb-innervating lateral motor column MNs (LMC-MNs) travel substantially to innervate distal limb mesenchyme. How LMC-MNs fine-tune the balance between survival and apoptosis while wiring the sensorimotor circuit en route remains unclear. Here, we show that the mir-17∼92 cluster is enriched in embryonic stem cell (ESC)-derived LMC-MNs and that conditional mir-17∼92 deletion in MNs results in the death of LMC-MNs in vitro and in vivo. mir-17∼92 overexpression rescues MNs from apoptosis, which occurs spontaneously during embryonic development. PTEN is a primary target of mir-17∼92 responsible for LMC-MN degeneration. Additionally, mir-17∼92 directly targets components of E3 ubiquitin ligases, affecting PTEN subcellular localization through monoubiquitination. This miRNA-mediated regulation modulates both target expression and target subcellular localization, providing LMC-MNs with an intricate defensive mechanism that controls their survival