[Gene-selective treatment approaches for Huntington's disease]. / Genselektive Therapieansätze bei der Huntington-Krankheit.

In Germany at least 8000 and probably up to ca. 14,000 people currently suffer from clinically manifest Huntington's disease (HD). In addition, an estimated 24,000 Germans carry the HD mutation in the huntingtin (HTT) gene and will develop HD during their lifetime. Although HD is a rare neurodegenerative disease, it is currently in the focus of general medical interest: clinical trials have begun that provide a rational basis for hope to slow down the so far relentless progression of the disease, ultimately resulting in patients becoming entirely dependent on nursing care. If treatment is started early enough it may be possible to mitigate the clinical manifestation of HD. These innovative therapeutic approaches aim at inhibiting the de novo production of mutant HTT gene products. A first clinical drug trial to demonstrate the efficacy (phase III) of intrathecal antisense oligonucleotides (ASO, active substance RG6042) was started in 2019. Additional clinical studies on alternative treatment approaches with allele-selective ASOs as well as gene therapeutic approaches using RNA molecules and zinc finger repressor complexes are imminent. This article gives an overview of the current gene-selective therapeutic approaches in HD under discussion.

Optimal search strategies of space-time coupled random walkers with finite lifetimes.

We present a simple paradigm for detection of an immobile target by a space-time coupled random walker with a finite lifetime. The motion of the walker is characterized by linear displacements at a fixed speed and exponentially distributed duration, interrupted by random changes in the direction of motion and resumption of motion in the new direction with the same speed. We call these walkers "mortal creepers." A mortal creeper may die at any time during its motion according to an exponential decay law characterized by a finite mean death rate ω(m). While still alive, the creeper has a finite mean frequency ω of change of the direction of motion. In particular, we consider the efficiency of the target search process, characterized by the probability that the creeper will eventually detect the target. Analytic results confirmed by numerical results show that there is an ω(m)-dependent optimal frequency ω=ω(opt) that maximizes the probability of eventual target detection. We work primarily in one-dimensional (d=1) domains and examine the role of initial conditions and of finite domain sizes. Numerical results in d=2 domains confirm the existence of an optimal frequency of change of direction, thereby suggesting that the observed effects are robust to changes in dimensionality. In the d=1 case, explicit expressions for the probability of target detection in the long time limit are given. In the case of an infinite domain, we compute the detection probability for arbitrary times and study its early- and late-time behavior. We further consider the survival probability of the target in the presence of many independent creepers beginning their motion at the same location and at the same time. We also consider a version of the standard "target problem" in which many creepers start at random locations at the same time.

A quasi-unidimensional granular chain to attenuate impact.

We study via numerical simulations a granular chain not only with decreasing radii (forward tapering) in geometric progression, but also decorated with grains positioned on the top and bottom of the chain, without altering its original length. The decorating grains act as an auxiliary chain which traps part of the energy and linear momentum, both propagating as a pulse due to disturbances produced at the end of the chain. Thus, this configuration optimizes the impact attenuation and aligns the chain naturally (by symmetry) which facilitates the construction of the experimental setup. Furtheremore, since the decorating grain radii increase along the chain, this new type of chain is necessarily short in order to avoid precompression. Nevertheless, even with short chains, it is possible to mitigate impacts almost completely.

Speeding chemical reactions by focusing.

We present numerical results for a chemical reaction of colloidal particles which are transported by a laminar fluid and are focused by periodic obstacles in such a way that the two components are well mixed and consequently the chemical reaction is speeded up. The roles of the various system parameters (diffusion coefficients, reaction rate, and obstacles sizes) are studied. We show that focusing speeds up the reaction from the diffusion limited rate ∼t(-1/2) to very close to the perfect mixing rate, ∼t(-1).

Asymptotic solutions of decoupled continuous-time random walks with superheavy-tailed waiting time and heavy-tailed jump length distributions.

We study the long-time behavior of decoupled continuous-time random walks characterized by superheavy-tailed distributions of waiting times and symmetric heavy-tailed distributions of jump lengths. Our main quantity of interest is the limiting probability density of the position of the walker multiplied by a scaling function of time. We show that the probability density of the scaled walker position converges in the long-time limit to a nondegenerate one only if the scaling function behaves in a certain way. This function as well as the limiting probability density are determined in explicit form. Also, we express the limiting probability density which has heavy tails in terms of the Fox H function and find its behavior for small and large distances.

Survival probability of a particle in a sea of mobile traps: a tale of tails.

We study the long-time tails of the survival probability P(t) of an A particle diffusing in d-dimensional media in the presence of a concentration rho of traps B that move subdiffusively, such that the mean square displacement of each trap grows as tgamma with 0 < or = gamma < or =1. Starting from a continuous time random walk description of the motion of the particle and of the traps, we derive lower and upper bounds for P(t) and show that for gamma < or =2/(d+2) these bounds coincide asymptotically, thus determining asymptotically exact results. The asymptotic decay law in this regime is exactly that obtained for immobile traps. This means that for sufficiently subdiffusive traps, the moving A particle sees the traps as essentially immobile, and Lifshitz or trapping tails remain unchanged. For gamma >2/(d+2) and d< or =2 the upper and lower bounds again coincide, leading to a decay law equal to that of a stationary particle. Thus, in this regime the moving traps see the particle as essentially immobile. For d>2 , however, the upper and lower bounds in this gamma regime no longer coincide, and the decay law for the survival probability of the A particle remains ambiguous.

Fine structure of the pygmy dipole resonance in (136)Xe.

The photoresponse of the semimagic N=82 nucleus (136)Xe was measured up to the neutron separation energy S(n) using the (gamma, gamma') reaction. A concentration of strong dipole excitations is observed well below S(n) showing a fragmented resonancelike structure. Microscopic calculations in the quasiparticle phonon model including complex configurations of up to three phonons agree well with the experimental data in the total integrated strength, in the shape and the fragmentation of the resonance, which allows us to draw conclusions on the damping mechanism of the pygmy dipole resonance.

From subdiffusion to superdiffusion of particles on solid surfaces.

We present a numerical and partially analytical study of classical particles obeying a Langevin equation that describes diffusion on a surface modeled by a two-dimensional potential. The potential may be either periodic or random. Depending on the potential and the damping, we observe superdiffusion, large-step diffusion, diffusion, and subdiffusion. Superdiffusive behavior is associated with low damping and is in most cases transient, albeit often long. Subdiffusive behavior is associated with highly damped particles in random potentials. In some cases subdiffusive behavior persists over our entire simulation and may be characterized as metastable. In any case, we stress that this rich variety of behaviors emerges naturally from an ordinary Langevin equation for a system described by ordinary canonical Maxwell-Boltzmann statistics.

Diffusion on a solid surface: anomalous is normal.

We present a numerical study of classical particles diffusing on a solid surface. The particles' motion is modeled by an underdamped Langevin equation with ordinary thermal noise. The particle-surface interaction is described by a periodic or a random two-dimensional potential. The model leads to a rich variety of different transport regimes, some of which correspond to anomalous diffusion such as has recently been observed in experiments and Monte Carlo simulations. We show that this anomalous behavior is controlled by the friction coefficient and stress that it emerges naturally in a system described by ordinary canonical Maxwell-Boltzmann statistics.

Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation.

The pathogenesis of Huntington's disease is still not completely understood. Several lines of evidence from toxic/non-transgenic animal models of Huntington's disease suggest that excitotoxic mechanisms may contribute to the pathological phenotype. Evidence from transgenic animal models of Huntington's disease, however, is sparse. To explore potential alterations in brain glutamate handling we studied transgenic mice expressing an N-terminal fragment of mutant huntingtin (R6/2). Intracerebral microdialysis in freely moving mice showed similar extracellular glutamate levels in R6/2 and littermate controls. However, partial inhibition of glutamate transport by L-trans-pyrrolidine-2,4-dicarboxylate (4 mM) disclosed an age-dependent increase in extracellular glutamate levels in R6/2 mice compared with controls, consistent with a reduction of functional glutamate transport capacity. Biochemical studies demonstrated an age-dependent downregulation of the glial glutamate transporter GLT-1 mRNA and protein, resulting in a progressive reduction of transporter function. Glutamate transporters other than GLT-1 were unchanged. In addition, increased extracellular glutamine levels and alterations to glutamine synthetase immunoreactivity suggested a perturbation of the glutamate-glutamine cycle. These findings demonstrate that the Huntington's disease mutation results in a progressively deranged glutamate handling in the brain, beginning before the onset of symptoms in mice. They also provide evidence for a contribution of excitotoxicity to the pathophysiology of Huntington's disease, and thus Huntington's disease may be added to the growing list of neurodegenerative disorders associated with compromised glutamate transport capacity.

Order statistics for d-dimensional diffusion processes.

We present results for the ordered sequence of first-passage times of arrival of N random walkers at a boundary in Euclidean spaces of d dimensions.

Energy relaxation in nonlinear one-dimensional lattices.

We study energy relaxation in thermalized one-dimensional nonlinear arrays of the Fermi-Pasta-Ulam type. The ends of the thermalized systems are placed in contact with a zero-temperature reservoir via damping forces. Harmonic arrays relax by sequential phonon decay into the cold reservoir, the lower-frequency modes relaxing first. The relaxation pathway for purely anharmonic arrays involves the degradation of higher-energy nonlinear modes into lower-energy ones. The lowest-energy modes are absorbed by the cold reservoir, but a small amount of energy is persistently left behind in the array in the form of almost stationary low-frequency localized modes. Arrays with interactions that contain both a harmonic and an anharmonic contribution exhibit behavior that involves the interplay of phonon modes and breather modes. At long times relaxation is extremely slow due to the spontaneous appearance and persistence of energetic high-frequency stationary breathers. Breather behavior is further ascertained by explicitly injecting a localized excitation into the thermalized arrays and observing the relaxation behavior.

Subdiffusion-limited A+A reactions.

We consider the coagulation dynamics A+A-->A and A+A <==> A and the annihilation dynamics A+A-->0 for particles moving subdiffusively in one dimension. This scenario combines the "anomalous kinetics" and "anomalous diffusion" problems, each of which leads to interesting dynamics separately and to even more interesting dynamics in combination. Our analysis is based on the fractional diffusion equation.

SCA7 mouse models show selective stabilization of mutant ataxin-7 and similar cellular responses in different neuronal cell types.

Accumulation of expanded polyglutamine proteins and selective pattern of neuronal loss are hallmarks of at least eight neurodegenerative disorders, including spinocerebellar ataxia type 7 (SCA7). We previously described SCA7 mice displaying neurodegeneration with progressive ataxin-7 accumulation in two cell types affected in the human pathology. We describe here a new transgenic model with a more widespread expression of mutant ataxin-7, including neuronal cell types unaffected in SCA7. In these mice a similar handling of mutant ataxin-7, including a cytoplasm to nucleus translocation and accumulation of N-terminal fragments, was observed in all neuronal populations studied. An extensive screen for chaperones, proteasomal subunits and transcription factors sequestered in nuclear inclusions (NIs) disclosed no pattern unique to neurons undergoing degeneration in SCA7. In particular, we found that the mouse TAF(II)30 subunit of the TFIID initiation complex is markedly accumulated in NIs, even though this protein does not contain a polyglutamine stretch. A striking discrepancy between mRNA and ataxin-7 levels in transgenic mice expressing the wild-type protein but not in those expressing the mutant one, indicates a selective stabilization of mutant ataxin-7, both in this model and the P7E/N model described previously. These mice therefore provide in vivo evidence that the polyglutamine expansion mutation can stabilize its target protein.

Thermal resonance in signal transmission.

We use temperature tuning to control signal propagation in simple one-dimensional arrays of masses connected by hard anharmonic springs and with no local potentials. In our numerical model a sustained signal is applied at one site of a chain immersed in a thermal environment and the signal-to-noise ratio is measured at each oscillator. We show that raising the temperature can lead to enhanced signal propagation along the chain, resulting in thermal resonance effects akin to the resonance observed in arrays of bistable systems.

Phase-induced stability in a parametric dimer.

We report results on a model of two coupled oscillators that undergo periodic parametric modulations with a phase difference straight theta. Being to a large extent analytically solvable, the model reveals a rich straight theta dependence of the regions of parametric resonance. In particular, the intuitive notion that antiphase modulations are less prone to parametric resonance is confirmed for sufficiently large coupling and damping. Some general results concerning synchronization properties in this system are presented. We also compare our results to a recently reported mean-field model of collective parametric instability, showing that the two-oscillator model captures much of the qualitative behavior of the infinite system.

Expanded polyglutamines induce neurodegeneration and trans-neuronal alterations in cerebellum and retina of SCA7 transgenic mice.

Among the eight progressive neurodegenerative diseases caused by polyglutamine expansions, spinocerebellar ataxia type 7 (SCA7) is the only one to display degeneration in both brain and retina. We show here that mice overexpressing full-length mutant ataxin-7[Q90] either in Purkinje cells or in rod photoreceptors have deficiencies in motor coordination and vision, respectively. In both models, although with different time courses, an N-terminal fragment of mutant ataxin-7 accumulates into ubiquitinated nuclear inclusions that recruit a distinct set of chaperone/proteasome subunits. A severe degeneration is caused by overexpression of ataxin-7[Q90] in rods, whereas a similar overexpression of normal ataxin-7[Q10] has no obvious effect. The degenerative process is not limited to photoreceptors, showing secondary alterations of post-synaptic neurons. These findings suggest that proteolytic cleavage of mutant ataxin-7 and trans-neuronal responses are implicated in the pathogenesis of SCA7.

Expression analysis of ataxin-7 mRNA and protein in human brain: evidence for a widespread distribution and focal protein accumulation.

Spinocerebellar ataxia 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG-trinucleotide repeat in the coding region of the SCA7 gene. The expansion is translated into an extended polyglutamine stretch in the protein ataxin-7, a protein of unknown function. By Northern blot analysis expression of ataxin-7 was detected in numerous regions of human brain and some peripheral tissues. It is unknown, however, if ataxin-7 is enriched at sites of the SCA7 pathology. We studied the regional and cellular expression pattern of ataxin-7 at the mRNA level by in situ hybridization histochemistry in normal human brain. Furthermore we used a monoclonal and two polyclonal antibodies raised against the normal ataxin-7 to establish the distribution of this protein in brain, retina and peripheral organs. At the mRNA level ataxin-7 was preferentially expressed in neurons; the regional distribution reflected neuronal packing density. Ataxin-7 immunoreactivity (IR) was similarly widely expressed. In most neurons, ataxin-7 IR was preferentially localized to the cytoplasmatic compartment although some nuclear ataxin-7 IR was detected in most neurons. A more intense and more prominently nuclear ataxin-7 IR was observed in neurons of the pons and the inferior olive, brain regions severly affected by the disease, suggesting that the subcellular localization and abundance of ataxin-7 is regulated in a regionally specific way. Since neurons displaying more intense and more prominently nuclear ataxin-7 IR belonged to the class of susceptible cells in SCA7, an enrichment of normal ataxin-7 in the nuclear compartment may contribute to neurodegeneration. However not all sites of SCA7 pathology displayed a strong cytoplasmatic and nuclear immunoreactivity.

Enhanced pulse propagation in nonlinear arrays of oscillators.

The propagation of a pulse in a nonlinear array of oscillators is influenced by the nature of the array and by its coupling to a thermal environment. For example, in some arrays a pulse can be speeded up while in others a pulse can be slowed down by raising the temperature. We begin by showing that an energy pulse (one dimension) or energy front (two dimensions) travels more rapidly and remains more localized over greater distances in an isolated array (microcanonical) of hard springs than in a harmonic array or in a soft-springed array. Increasing the pulse amplitude causes it to speed up in a hard chain, leaves the pulse speed unchanged in a harmonic system, and slows down the pulse in a soft chain. Connection of each site to a thermal environment (canonical) affects these results very differently in each type of array. In a hard chain the dissipative forces slow down the pulse while raising the temperature speeds it up. In a soft chain the opposite occurs: the dissipative forces actually speed up the pulse, while raising the temperature slows it down. In a harmonic chain neither dissipation nor temperature changes affect the pulse speed. These and other results are explained on the basis of the frequency vs energy relations in the various arrays.