Genomic and Proteomic Biomarker Discovery in Neurological Disease

Technology for high-throughout scanning of the human genome and its encoded proteins have rapidly developed to allow systematic analyses of human disease. Application of these technologies is becoming an increasingly effective approach for identifying the biological basis of genetically complex neurological diseases. This review will highlight significant findings resulting from the use of a multitude of genomic and proteomic technologies toward biomarker discovery in neurological disorders. Though substantial discoveries have been made, there is clearly significant promise and potential remaining to be fully realized through increasing use of and further development of -omic technologies

Tau immunoreactivity in peripheral tissues of human aging and select tauopathies

Many studies have been directed at understanding mechanisms of tau aggregation and therapeutics, nearly all focusing on the brain. It is critical to understand the presence of tau in peripheral tissues since this may provide new insights into disease progression and selective vulnerability. The current study sought to determine the presence of select tau species in peripheral tissues in elderly individuals and across an array of tauopathies. Using formalin fixed paraffin embedded sections, we examined abdominal skin, submandibular gland, and sigmoid colon among 69 clinicopathologically defined cases: 19 lacking a clinical neuropathological diagnosis (normal controls), 26 progressive supranuclear palsy (PSP), 21 Alzheimer's disease (AD), and 3 with corticobasal degeneration (CBD). Immunohistochemistry was performed using antibodies for "total" tau (HT7) and two phosphorylated tau species (AT8 and pT231). HT7 staining of abdominal skin revealed immunoreactivity of potential nerve elements in 5% of cases (1 AD, 1 AD/PSP, and 1 CBD out of 55 cases examined); skin sections lacked AT8 and pT231 immunoreactive nerve elements. Submandibular glands from all cases had HT7 immunoreactive nerve elements; while pT231 was present in 92% of cases, and AT8 in only 3 cases (2 AD and one AD/PSP case). In sigmoid colon, HT7 immunoreactivity was present in all but 2 cases (97%), pT231 in 54%, and AT8 was present in only 5/62 cases (8%). These data suggest select tau species in CNS tauopathies do not have a high propensity to spread to the periphery and this may hold clues for the understanding of CNS tau pathogenicity and vulnerability

Essential Tremor in the Elderly and Risk for Dementia

The objective is to examine the risk of dementia in subjects with essential tremor (ET) involved in the Arizona Study of Aging and Neurodegenerative Disorders. All subjects were free of a neurodegenerative diagnosis at baseline and had annual motor, general neurological, and neuropsychological assessments. Subjects with ET were compared with controls for the risk of dementia. There were 83 subjects with ET and 424 subjects without tremor. Mean age at study entry was 80±5.9 for ET and 76±8.5 for controls. Median tremor duration was 5.2 years at study entry. Followup was a median of 5.4 years (range 0.9 to 12.1). The hazard ratio for the association between ET and dementia was 0.79 (95% CI 0.33 to 1.85). The hazard ratio for the association between tremor onset at age 65 or over, versus onset before age 65, was 2.1 (95% CI 0.24 to 18) and the hazard ratio for the association between tremor duration greater than 5 years, versus less than 5 years, was 0.46 (95% CI 0.08 to 2.6). We conclude that all elderly ET was not associated with an increased risk of dementia but that a subset of subjects with older age onset/shorter duration tremor may be at higher risk

High-content siRNA screening of the kinome identifies kinases involved in Alzheimer's disease-related tau hyperphosphorylation

<p>Abstract</p> <p>Background</p> <p>Neurofibrillary tangles (NFT), a cardinal neuropathological feature of Alzheimer's disease (AD) that is highly correlated with synaptic loss and dementia severity, appear to be partly attributable to increased phosphorylation of the microtubule stabilizing protein tau at certain AD-related residues. Identifying the kinases involved in the pathologic phosphorylation of tau may provide targets at which to aim new AD-modifying treatments.</p> <p>Results</p> <p>We report results from a screen of 572 kinases in the human genome for effects on tau hyperphosphorylation using a loss of function, high-throughput RNAi approach. We confirm effects of three kinases from this screen, the eukaryotic translation initiation factor 2 α kinase 2 (EIF2AK2), the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), and the A-kinase anchor protein 13 (AKAP13) on tau phosphorylation at the 12E8 epitope (serine 262/serine 356). We provide evidence that EIF2AK2 effects may result from effects on tau protein expression, whereas DYRK1A and AKAP13 are likely more specifically involved in tau phosphorylation pathways.</p> <p>Conclusions</p> <p>These findings identify novel kinases that phosphorylate tau protein and provide a valuable reference data set describing the kinases involved in phosphorylating tau at an AD-relevant epitope.</p

Selective Estrogen Receptor Down-Regulator and Selective Estrogen Receptor Modulators Differentially Regulate Lactotroph Proliferation

occupation, differentially modulates the biological outcome of anti-estrogens. expression and release, as well as ERE-mediated transcriptional activity. expression

Targeted Skipping of Human Dystrophin Exons in Transgenic Mouse Model Systemically for Antisense Drug Development

Antisense therapy has recently been demonstrated with great potential for targeted exon skipping and restoration of dystrophin production in cultured muscle cells and in muscles of Duchenne Muscular Dystrophy (DMD) patients. Therapeutic values of exon skipping critically depend on efficacy of the drugs, antisense oligomers (AOs). However, no animal model has been established to test AO targeting human dystrophin exon in vivo systemically. In this study, we applied Vivo-Morpholino to the hDMD/mdx mouse, a transgenic model carrying the full-length human dystrophin gene with mdx background, and achieved for the first time more than 70% efficiency of targeted human dystrophin exon skipping in vivo systemically. We also established a GFP-reporter myoblast culture to screen AOs targeting human dystrophin exon 50. Antisense efficiency for most AOs is consistent between the reporter cells, human myoblasts and in the hDMD/mdx mice in vivo. However, variation in efficiency was also clearly observed. A combination of in vitro cell culture and a Vivo-Morpholino based evaluation in vivo systemically in the hDMD/mdx mice therefore may represent a prudent approach for selecting AO drug and to meet the regulatory requirement

Improve in-depth immunological risk assessment to optimize genetic-compatibility and clinical outcomes in child and adolescent recipients of parental donor kidney transplants: protocol for the INCEPTION study.

BACKGROUND: Parental donor kidney transplantation is the most common treatment option for children and adolescents with kidney failure. Emerging data from observational studies have reported improved short- and medium-term allograft outcomes in recipients of paternal compared to maternal donors. The INCEPTION study aims to identify potential differences in immunological compatibility between maternal and paternal donor kidneys and ascertain how this affects kidney allograft outcomes in children and adolescents with kidney failure. METHODS: This longitudinal observational study will recruit kidney transplant recipients aged ≤18 years who have received a parental donor kidney transplant across 4 countries (Australia, New Zealand, United Kingdom and the Netherlands) between 1990 and 2020. High resolution human leukocyte antigen (HLA) typing of both recipients and corresponding parental donors will be undertaken, to provide an in-depth assessment of immunological compatibility. The primary outcome is a composite of de novo donor-specific anti-HLA antibody (DSA), biopsy-proven acute rejection or allograft loss up to 60-months post-transplantation. Secondary outcomes are de novo DSA, biopsy-proven acute rejection, acute or chronic antibody mediated rejection or Chronic Allograft Damage Index (CADI) score of > 1 on allograft biopsy post-transplant, allograft function, proteinuria and allograft loss. Using principal component analysis and Cox proportional hazards regression modelling, we will determine the associations between defined sets of immunological and clinical parameters that may identify risk stratification for the primary and secondary outcome measures among young people accepting a parental donor kidney for transplantation. This study design will allow us to specifically investigate the relative importance of accepting a maternal compared to paternal donor, for families deciding on the best option for donation. DISCUSSION: The INCEPTION study findings will explore potentially differential immunological risks of maternal and paternal donor kidneys for transplantation among children and adolescents. Our study will provide the evidence base underpinning the selection of parental donor in order to achieve the best projected long-term kidney transplant and overall health outcomes for children and adolescents, a recognized vulnerable population. TRIAL REGISTRATION: The INCEPTION study has been registered with the Australian New Zealand Clinical Trials Registry, with the trial registration number of ACTRN12620000911998 (14th September 2020)