Familial Spinocerebellar Ataxia Type 2 Parkinsonism Presenting as Intractable Oromandibular Dystonia

We have previously described a Korean family afflicted with spinocerebellar ataxia type 2 (SCA2) parkinsonism in which genetic analysis revealed CAG expansion of 40 repeats in the ATXN2 gene.1 The affected members presented with levodopa-responsive parkinsonism without cerebellar ataxia. Some showed motor fluctuation and dyskinesia, further mimicking idiopathic Parkinson’s disease (PD). Herein, we report a member of this family who developed jaw-opening and lingual-protrusion dystonia as the chief presentation

Catalytic enzymes are active matter

Using a microscopic theory to analyze experiments, we demonstrate that enzymes are active matter. Superresolution fluorescence measurements—performed across four orders of magnitude of substrate concentration, with emphasis on the biologically relevant regime around or below the Michaelis–Menten constant—show that catalysis boosts the motion of enzymes to be superdiffusive for a few microseconds, enhancing their effective diffusivity over longer timescales. Occurring at the catalytic turnover rate, these fast ballistic leaps maintain direction over a duration limited by rotational diffusion, driving enzymes to execute wormlike trajectories by piconewton forces performing work of a few kBT against viscosity. The boosts are more frequent at high substrate concentrations, biasing the trajectories toward substrate-poor regions, thus exhibiting antichemotaxis, demonstrated here experimentally over a wide range of aqueous concentrations. Alternative noncatalytic, passive mechanisms that predict chemotaxis, cross-diffusion, and phoresis, are critically analyzed. We examine the physical interpretation of our findings, speculate on the underlying mechanism, and discuss the avenues they open with biological and technological implications. These findings violate the classical paradigm that chemical reaction and motility are distinct processes, and suggest reaction–motion coupling as a general principle of catalysis.11sciescopu

Enzyme leaps fuel antichemotaxis

There is mounting evidence that enzyme diffusivity is enhanced when the enzyme is catalytically active. Here, using superresolution microscopy [stimulated emission-depletion fluorescence correlation spectroscopy (STED-FCS)], we show that active enzymes migrate spontaneously in the direction of lower substrate concentration (???antichemotaxis???) by a process analogous to the run-and-tumble foraging strategy of swimming microorganisms and our theory quantifies the mechanism. The two enzymes studied, urease and acetylcholinesterase, display two families of transit times through subdiffraction-sized focus spots, a diffusive mode and a ballistic mode, and the latter transit time is close to the inverse rate of catalytic turnover. This biochemical information-processing algorithm may be useful to design synthetic self-propelled swimmers and nanoparticles relevant to active materials. Executed by molecules lacking the decision-making circuitry of microorganisms, antichemotaxis by this run-and-tumble process offers the biological function to homogenize product concentration, which could be significant in situations when the reactant concentration varies from spot to spot

Master curve of boosted diffusion for 10 catalytic enzymes

Molecular agitation more rapid than thermal Brownian motion is reported for cellular environments, motor proteins, synthetic molecular motors, enzymes, and common chemical reactions, yet that chemical activity coupled to molecular motion contrasts with generations of accumulated knowledge about diffusion at equilibrium. To test the limits of this idea, a critical testbed is the mobility of catalytically active enzymes. Sentiment is divided about the reality of enhanced enzyme diffusion, with evidence for and against. Here a master curve shows that the enzyme diffusion coefficient increases in proportion to the energy release rate-the product of MichaelisMenten reaction rate and Gibbs free energy change (Delta G)-with a highly satisfactory correlation coefficient of 0.97. For 10 catalytic enzymes (urease, acetylcholinesterase, seven enzymes from the glucose cascade cycle, and one other), our measurements span from a roughly 40% enhanced diffusion coefficient at a high turnover rate and negative Delta G to no enhancement at a slow turnover rate and positive Delta G. Moreover, two independent measures of mobility show consistency, provided that one avoids undesirable fluorescence photophysics. The master curve presented here quantifies the limits of both ideas, that enzymes display enhanced diffusion and that they do not within instrumental resolution, and has possible implications for understanding enzyme mobility in cellular environments. The striking linear dependence of Delta G for the exergonic enzymes (Delta G 0), together with the vanishing effect for endergonic enzyme (Delta G 0), are consistent with a physical picture in which the mechanism boosting the diffusion is an active one, utilizing the available work from the chemical reaction

Enzyme leaps fuel antichemotaxis

There is mounting evidence that enzyme diffusivity is enhanced when the enzyme is catalytically active. Here, using superresolution microscopy [stimulated emission-depletion fluorescence correlation spectroscopy (STED-FCS)], we show that active enzymes migrate spontaneously in the direction of lower substrate concentration (???antichemotaxis???) by a process analogous to the run-and-tumble foraging strategy of swimming microorganisms and our theory quantifies the mechanism. The two enzymes studied, urease and acetylcholinesterase, display two families of transit times through subdiffraction-sized focus spots, a diffusive mode and a ballistic mode, and the latter transit time is close to the inverse rate of catalytic turnover. This biochemical information-processing algorithm may be useful to design synthetic self-propelled swimmers and nanoparticles relevant to active materials. Executed by molecules lacking the decision-making circuitry of microorganisms, antichemotaxis by this run-and-tumble process offers the biological function to homogenize product concentration, which could be significant in situations when the reactant concentration varies from spot to spot