Research Round-Up

By: Lise Munsie, PhD

In the proteome…

A number of studies suggest a relationship between huntingtin (HTT) and tau protein pathology which has yet to be elucidated. Tau is found predominantly in neurons. In tauopathies such as Alzheimer disease, tau is cleaved and then aggregates. A study by Gratuze and colleagues looks at the phosphorylation state of tau in both the R6/2 and Q175 mouse models of HD.1 Hyperphosphorylation of tau at different positions can be seen in the presence of mutant huntingtin (mHtt). The authors attribute this hyperphosphorylation to a down-regulation of calcineurin phosphatase caused by mHtt. Hyperphosphorylation of tau is not associated with increased cleavage or aggregation.

Two recent publications from the Outeiro group expand these observations. The first examines how mHTT impacts tau localization, molecular interactions and phosphorylation pattern.2 Using biophotonics, they show that mHTT leads not only to altered phosphorylation of tau, but also alters tau’s cellular localization and microtubule stabilizing functions. They describe a new kind of aggregate containing tau and mHTT, and hypothesize that an aberrant interaction with mHTT may leave tau unable to interact with phosphatases.

In a second manuscript in Human Molecular Genetics, the group investigates the interaction between HTT and α- synuclein, a protein that aggregates and causes toxicity in Parkinson disease (PD), in a Drosophila model.3 The authors show that co-expression of α-synuclein and mHtt leads to an increase in insoluble aggregates containing both proteins, leading to motor deficits and decreased life span. The coexpression of these proteins synergistically enhances toxicity, accelerating the progression of the disorder. This system may be useful for screening potential drug candidates for both HD and PD.

1 Gratuze M, Noël A, Julien C, et al. Tau hyperphosphorylation and deregulation of calcineurin in mouse models of Huntington’s disease. Hum Mol Genet. 2015 Jan 1; 24(1):86-99. doi:10.1093/hmg/ddu456. Epub 2014 Sep 8.

2 Blum D, Herrera F, Francelle L, et al. Mutant huntingtin alters Tau phosphorylation and subcellular distribution. Hum Mol Genet. 2015 Jan 1; 24(1):76-85. doi: 10.1093/hmg/ddu421. Epub 2014 Aug 20.

3 Pocas GM, Branco-Santos J, Herrera F, et al. α-Synuclein modifies mutant huntingtin aggregation and neurotoxicity in Drosophila. Hum Mol Genet. 2014 Dec 1. pii: ddu606. [Epub ahead of print].

In the neurons…

neuronA report by Yao and colleagues in Molecular and Cellular Neuroscience describes an unbiased proteomics approach to screen for HTT interactors in synaptosome preparations of brain regions affected in HD.1 A large amount of HTT was found in the synaptosome fraction. HTT was also found to interact with components of the presynaptic cytomatrix: specifically, the Bassoon, Piccolo and Ahnak proteins, components of the cytomatrix at active zone complex. The authors posit that HTT acts as a scaffold, and forms part of the complex that regulates endo- and exocytosis of synaptic vesicles. Pietropaolo and colleagues report in Neuropharmacology on their investigation of the role of the endocannabanoid system (ECS) in the etiology of HD.2 The ECS modulates brain function in brain regions affected by HD, and has been implicated in HD gene expression. Pietropaolo’s group administered the cannabinoid receptor agonist WIN to R6/1 mice acutely or chronically, then monitored motor and social behavior and neurodegeneration. Chronic administration showed improvements in motor behaviors and decreased degeneration of medium spiny neurons with an increase in inclusions, suggesting a positive influence of aggregates and potential therapeutic benefit of ECS modulation.

A study by the Brouillet group in Human Molecular Genetics examines preferential degeneration of the striatum in HD.3 They look at Crym, an NADPH-dependent p38 cytosolic T3-binding protein that is preferentially expressed in the striatum. The expression of Crym is reduced in full length BACHD and knock-in models of HD, even prior to neurodegeneration. Overexpression of Crym in fragment models of HD also reduces toxicity, suggesting that Crym may be another therapeutic target for HD.

1 Yao J, Ong SE, Bajjalieh S. Huntingtin is associated with cytomatrix proteins at the presynaptic terminal. Mol Cell Neurosci. 2014 Nov 4;63C:96-100. doi: 10.1016/j.mcn.2014.10.003. [Epub ahead of print]

2 Pietropaolo S, Bellocchio L, Ruiz-Calvo A, et al. Chronic cannabinoid receptor stimulation selectively prevents motor impairments in a mouse model of Huntington’s disease. Neuropharmacology. 2015 Feb; 89:368-74. doi: 10.1016/j.neuropharm.2014.07.021. Epub 2014 Aug 11.

3 Francelle L, Galvan L, Gaiullard M, et al. Loss of the thyroid hormone binding protein Crym renders striatal neurons more vulnerable to mutant huntingtin in Huntington’s disease. Hum Mol Genet. 2014 Nov 14. pii: ddu571. [Epub ahead of print].

In the clinic…

A recent article by Sussmuth and colleagues published by the PADDINGTON consortium outlines their trial of the safety, tolerability, and deliverability of the SIRT1 inhibitor Selistat for HD patients.1 SIRT1 has been shown to acetylate mHTT, leading to altered transcription. Selistat is a selective SIRT1 inhibitor, as inhibiting SIRT1 has shown therapeutic effects in model organisms. Sussmuth’s group performed a randomized, double blind, placebo-controlled study and found that Selistat is safe and well tolerated in patients with early HD. Importantly, blood plasma contained levels of the drug that have therapeutic effects in model organisms. Tetrabenazine, currently the only FDA approved drug for treatment of HD-related chorea, has many adverse effects, including worsening psychological symptoms such as depression. The Haghighi group in Sweden performed a small study evaluating the safety and efficacy of (−)-OSU6162, a monoaminergic stabilizer that acts on dopaminergic and serotonergic receptors.2

No such psychological adverse effects were associated with the administration of the drug. The researchers noted positive trends in both psychological and motor assessments, suggesting that this class of compound may warrant larger clinical trials in HD.

The PREDICT-HD group published a new study evaluating how measures other than CAG repeat length correlate with age of onset of HD symptoms, to assist in clinical trial design and prognosis3. There were 40 different measures taken on over 1,000 patients, including imaging, motor, psychiatric, functional, and cognitive measures. The group found several measures that can improve the diagnosis of onset of HD, the strongest being total motor score, putamen volume and the Stroop word test. The results will inform the selection of outcomes for future clinical trials.

1 Sussmuth SD, Haider S, Landwehrmeyer GB, et al. An Exploratory Double blind, Randomised Clinical Trial with Selisistat, a SirT1 Inhibitor, in Patients with Huntington’s Disease. British journal of clinical pharmacology 2014.

2 Kloberg A, Constantinescu R, Nilsson MK, et al. Tolerability and efficacy of the monoaminergic stabilizer (-)-OSU6162 (PNU-96391A) in Huntington’s disease: a double-blind crossover study. Acta neuropsychiatrica 2014; 26:298-306.

3 Paulsen JS, Long JD, Ross CA, et al. Prediction of manifest Huntington’s disease with clinical and imaging measures: a prospective observational study. Lancet Neurol. 2014 Dec;