Huntingtin turnover: modulation of huntingtin degradation by cAMP-dependent protein kinase A (PKA) phosphorylation of C-HEAT domain Ser2550
Huntington’s disease (HD) is a neurodegenerative disorder caused by an inherited unstable HTT CAG repeat that expands further, thereby eliciting a disease process that may be initiated by polyglutamine-expanded huntingtin or a short polyglutamine-product. Phosphorylation of selected candidate residues is reported to mediate polyglutamine-fragment degradation and toxicity. In this manuscript, CGM Investigators Ihn Sik Seong, Marcy MacDonald and colleagues used deep mass spectrometry-based phosphoproteomics to systematically identify sites in purified huntingtin and in the endogenous protein. The analyses identified as many as 95 total phospho-sites in Huntingtin, including phosphorylation of C-HEAT Ser2550 by AMP-dependent protein kinase (PKA), which was found to hasten huntingtin degradation. This work highlights categories of phosphosites and biological processes that regulate huntingtin degradation that are relevant to HD pathogenesis and merit further study.
Long-term effects of l-serine supplementation upon a mouse model of diabetic neuropathy
Deoxysphingolipids (1-deoxySLs) are neurotoxic sphingolipids associated with obesity and diabetic neuropathy (DN) and have been linked to severity of functional peripheral neuropathies. L-serine supplementation can reduce 1-deoxySL accumulation and improve insulin sensitivity and sensory nerve velocity, but long-term outcomes have not yet been examined. In this work published by CGM investigator Florian Eichler and colleagues, a preclinical model of diabetic neuropathy was treated oral l-serine and longitudinally quantified the extent of functional neuropathy progression. Functional neuropathy and sensory modalities were significantly improved in the treatment group well into advanced stages of disease, however, structural assessments revealed prominent axonal degeneration, apoptosis and Schwann cell pathology, suggesting that neuropathy was ongoing. Thus, despite significant functional improvements, L-serine does not prevent chronic degenerative changes specifically at the structural level, pointing to other processes such as oxidative damage and hyperglycemia that may have additional pathological effects in DN.
Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms
Pathogenic SRY-box transcription factor 2 (SOX2) variants typically cause severe ocular defects within a SOX2 disorder spectrum that includes hypogonadotropic hypogonadism. In this work published by CGM associate member Ravi Balasubramanian, CGM senior associate member Stephanie Seminara, and CGM investigator Bill Crowley, exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH) was mined for pathogenic SOX2 variants. They identified 8 IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes, going on to determine that Sox2 is highly expressed in the hypothalamus of adult mice and colocalized with kisspeptin 1 (KISS1) expression, and suppression of mouse SOX2 protein increased the levels of human kisspeptin, which has previously been invoked in IHH. These data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH, and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.
Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma
Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies. In this manuscript by CGM investigator Vijaya Ramesh and colleagues, data from previous high-throughput drug screening in NF2 preclinical models was leveraged to identify a class of compounds targeting the ubiquitin-proteasome pathway (UPP) that may have utility in NF2. Through a series of elaborate investigation of these UPP targeting agents in vitro and in vivo, the group found that treatment delayed tumor growth, suggesting a therapeutic potential. This important work in preclinical models lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.
Clonal hematopoiesis of indeterminate potential (CHIP), a condition defined by a set of aging-related genetic mutations in blood cells, is associated with an increased risk of several conditions. A team led by CGM PI Pradeep Natarajan and colleagues from Centro Nacional de Investigaciones Cardiovasculares, Stanford University, and Vanderbilt University explored the relationship between CHIP and atherosclerosis in the peripheral arteries. Individuals with mutations in DNA damage repair genes had an increased risk, and mouse data indicated that such mutations may drive increased aortic plaque size and accumulation of macrophages within plaques.
For many monogenic traits, the genetic variants that underpin those traits act in dominant (i.e. one copy of the variant is sufficient to manifest the trait) or recessive (i.e., two copies are required). For polygenic traits driven by many different variants scattered across the genome, however, whether the associated variants act in an additive or dominant fashion is less clear. To explore this question, Duncan Palmer, Alex Bloemendal, Ben Neale, and colleagues developed dominance LD score regression (d-LDSC) and applied it to UK Biobank data on 1,060 traits finding that for most complex traits dosage-dependent additive effects account for the overwhelming majority of heritable trait variation.
Diverse data expand what’s known about IBD genetics
Inflammatory bowel diseases (IBDs) are globally prevalent and heavily influenced by genetics, but the majority of genetic data collected about them have come from people of European ancestry. CGM faculty member, Hailiang Huang, describe the largest IBD genetics study to date in East Asian populations. Their data revealed 80 new IBD-associated genetic loci just in people from East Asia, and 320 loci when analyzed together with data from European individuals. The team also constructed a new, more accurate polygenic score for IBD risk.
The limited information regarding molecular targets and genetic factors in current treatments for type 2 diabetes (T2D) hampers doctors’ and researchers’ ability to predict response and adverse effects in patients. Using data from a clinical study called SUGAR-MGH, CGM faculty members, Jose Florez and Miriam Udler, and colleagues investigated how genetic variations affect the response to the glucose-lowering medications, glipizide and metformin, in individuals with T2D. After genotyping 1,000 participants (at risk for developing T2D) from diverse ancestries in the study, the team discovered new variations related to the effectiveness of these medications and gained insights into the underlying mechanisms of T2D.
Cardiometabolic profiles in children and adults with overweight and obesity and down syndrome
Being obese is associated with an increased cardiometabolic risk in the general population. While individuals with Down syndrome are at increased risk for being overweight and obese, the associated cardiometabolic risk in this population is not clear. This new studyhelps clarify this risk. Dr. Skotko and his colleagues performed a cross-sectional anthropometric and clinical laboratory data were collected on 240 patients between the ages of 3 and 63 years across 7 international sites. Distributive percentiles were calculated for common cardiometabolic biomarkers, with adjusted models testing for adiposity as a predictor of cardiometabolic risk. Most cardiometabolic biomarker profiles showed distributive values within normal ranges in both children and adults. The data suggest that in contrast to the general population, in individuals with Down syndrome, being overweight and obese does not appear to confer a significantly increased risk for cardiometabolic disease by biomarker profile. Individuals with DS who are overweight/obese appear to have unique cardiometabolic profiles unrelated to adiposity, notable for increased hs-CRP and normal HA1c levels.
The Center for Genomic Medicine (CGM) comprises one of the largest and most vibrant hubs of genomic medicine research in the world. The CGM includes 46 faculty collaborating to define the ‘genomic medicine cycle’ – which envisages a genomics community seeking to advance research from basic genomics research to ultimately using genome information for diagnostics and targeted therapeutics. All of our investigators are faculty at Harvard Medical School, and many members of our community are also investigators at the Broad Institute of Harvard and MIT.