TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau.

Tau protein plays an important role in the biology of stress granules and in the stress response of neurons, but the nature of these biochemical interactions is not known. Here we show that the interaction of tau with RNA and the RNA binding protein TIA1 is sufficient to drive phase separation of tau at physiological concentrations, without the requirement for artificial crowding agents such as polyethylene glycol (PEG). We further show that phase separation of tau in the presence of RNA and TIA1 generates abundant tau oligomers. Prior studies indicate that recombinant tau readily forms oligomers and fibrils in vitro in the presence of polyanionic agents, including RNA, but the resulting tau aggregates are not particularly toxic. We discover that tau oligomers generated during copartitioning with TIA1 are significantly more toxic than tau aggregates generated by incubation with RNA alone or phase-separated tau complexes generated by incubation with artificial crowding agents. This pathway identifies a potentially important source for generation of toxic tau oligomers in tau-related neurodegenerative diseases. Our results also reveal a general principle that phase-separated RBP droplets provide a vehicle for coassortment of selected proteins. Tau selectively copartitions with TIA1 under physiological conditions, emphasizing the importance of TIA1 for tau biology. Other RBPs, such as G3BP1, are able to copartition with tau, but this happens only in the presence of crowding agents. This type of selective mixing might provide a basis through which membraneless organelles bring together functionally relevant proteins to promote particular biological activities.

Heavy Metal Neurotoxicants Induce ALS-Linked TDP-43 Pathology.

Heavy metals, such as lead, mercury, and selenium, have been epidemiologically linked with a risk of ALS, but a molecular mechanism proving the connection has not been shown. A screen of putative developmental neurotoxins demonstrated that heavy metals (lead, mercury, and tin) trigger accumulation of TDP-43 into nuclear granules with concomitant loss of diffuse nuclear TDP-43. Lead (Pb) and methyl mercury (MeHg) disrupt the homeostasis of TDP-43 in neurons, resulting in increased levels of transcript and increased splicing activity of TDP-43. TDP-43 homeostasis is tightly regulated, and positively or negatively altering its splicing-suppressive activity has been shown to be deleterious to neurons. These changes are associated with the liquid-liquid phase separation of TDP-43 into nuclear bodies. We show that lead directly facilitates phase separation of TDP-43 in a dose-dependent manner in vitro, possibly explaining the means by which lead treatment results in neuronal nuclear granules. Metal toxicants also triggered the accumulation of insoluble TDP-43 in cultured cells and in the cortices of exposed mice. These results provide novel evidence of a direct mechanistic link between heavy metals, which are a commonly cited environmental risk of ALS, and molecular changes in TDP-43, the primary pathological protein accumulating in ALS.

Enhanced motor function and its neurophysiological correlates after navigated low-frequency repetitive transcranial magnetic stimulation over the contralesional motor cortex in stroke.

BACKGROUND: The net effect of altered interhemispheric interactions between homologous motor cortical areas after unilateral stroke has been previously reported to contribute to residual hemiparesis. Using this framework, we hypothesized that navigated 1 Hz repetitive transcranial magnetic stimulation (rTMS) over the contralesional hemisphere would induce a stronger physiological and behavioural response in patients with residual motor deficit than in healthy subjects, because an imbalance in interhemispheric excitability may underlie motor dysfunction. METHODS: Navigated rTMS was conducted in 8 chronic stroke patients (67.50±13.77 years) and in 8 comparable normal subjects (57.38±9.61 years). We evaluated motor function (Finger tapping, Nine Hole Peg test, Strength Index and Reaction Time) as well as the excitatory and inhibitory function (resting motor threshold, motor evoked potential amplitude, intra-cortical inhibition and facilitation, and silent period) of the stimulated and non-stimulated motor cortex before and after navigated rTMS. RESULTS: rTMS induced an increase in excitability in the ipsilesional (non-stimulated) motor cortex and led to improved performance in the finger tapping task and pinch force task. These physiological and behavioral effects were more prominent (or robust) in the group of stroke patients than in the control group. CONCLUSION: Navigated low-frequency rTMS involving precise and consistent targeting of the contralesional hemisphere in stroke patients enhanced the cortical excitability of the ipsilesional hemisphere and the motor response of the hemiparetic hand.

Changes in cortical plasticity across the lifespan.

Deterioration of motor and cognitive performance with advancing age is well documented, but its cause remains unknown. Animal studies dating back to the late 1970s reveal that age-associated neurocognitive changes are linked to age-dependent changes in synaptic plasticity, including alterations of long-term potentiation and depression (LTP and LTD). Non-invasive brain stimulation techniques enable measurement of LTP- and LTD-like mechanisms of plasticity, in vivo, in humans, and may thus provide valuable insights. We examined the effects of a 40-s train of continuous theta-burst stimulation (cTBS) to the motor cortex (600 stimuli, three pulses at 50 Hz applied at a frequency of 5 Hz) on cortico-spinal excitability as measured by the motor evoked potentials (MEPs) induced by single-pulse transcranial magnetic stimulation before and after cTBS in the contralateral first dorsal interosseus muscle. Thirty-six healthy individuals aged 19-81 years old were studied in two sites (Boston, USA and Barcelona, Spain). The findings did not differ across study sites. We found that advancing age is negatively correlated with the duration of the effect of cTBS (r = -0.367; p = 0.028) and the overall amount of corticomotor suppression induced by cTBS (r = -0.478; p = 0.003), and positively correlated with the maximal suppression of amplitude on motor evoked responses in the target muscle (r = 0.420; p = 0.011). We performed magnetic resonance imaging (MRI)-based individual morphometric analysis in a subset of subjects to demonstrate that these findings are not explained by age-related brain atrophy or differences in scalp-to-brain distance that could have affected the TBS effects. Our findings provide empirical evidence that the mechanisms of cortical plasticity area are altered with aging and their efficiency decreases across the human lifespan. This may critically contribute to motor and possibly cognitive decline.

The many places of frequency: evidence for a novel locus of the lexical frequency effect in word production.

The effect of lexical frequency on language-processing tasks is exceptionally reliable. For example, pictures with higher frequency names are named faster and more accurately than those with lower frequency names. Experiments with normal participants and patients strongly suggest that this production effect arises at the level of lexical access. Further work has suggested that within lexical access this effect arises at the level of lexical representations. Here we present patient E.C. who shows an effect of lexical frequency on his nonword error rate. The best explanation of his performance is that there is an additional locus of frequency at the interface of lexical and segmental representational levels. We confirm this hypothesis by showing that only computational models with frequency at this new locus can produce a similar error pattern to that of patient E.C. Finally, in an analysis of a large group of Italian patients, we show that there exist patients who replicate E.C.'s pattern of results and others who show the complementary pattern of frequency effects on semantic error rates. Our results combined with previous findings suggest that frequency plays a role throughout the process of lexical access.

Evaluating computational models in cognitive neuropsychology: the case from the consonant/vowel distinction.

Caramazza et al. [Caramazza, A., Chialant, D., Capasso, R., & Miceli, G. (2000). Separable processing of consonants and vowels. Nature, 403(6768), 428-430.] report two patients who exhibit a double dissociation between consonants and vowels in speech production. The patterning of this double dissociation cannot be explained by appealing to sub-phonemic distinctions, such as sonority level or damage to specific phonological features. They argue that consonant/vowel status is an autonomous level of representation. Monaghan and Shillcock [Monaghan, P., & Shillcock, R. (2003). Connectionist modelling of the separable processing of consonants and vowels. Brain and Language, 86(1), 83-98.] present computational models which supposedly exhibit a similar double dissociation. They contend that these models can explain the patient data, without appeal to such supra-phonemic distinctions as consonant/vowel status. Here we argue that their claim fails to meet two necessary criteria. Their models do not fit the pattern of the patient data, either quantitatively or qualitatively. Furthermore, the motivation for these models is unclear beyond just being an attempt to explain this specific phenomenon. We conclude that these models, in their current form, do not provide an alternative explanation to the representation of consonants and vowels.

The locus of the frequency effect in picture naming: when recognizing is not enough.

The lexical frequency effect in picture naming is generally assumed to constitute a signature of lexical access. Lexical frequency, however, is correlated with other variables, like concept familiarity, that can produce effects similar to those of lexical frequency in picture naming tasks. In this study, a delayed picture naming task was employed to address the hypothesis that the frequency effect in picture naming is due to variables that affect processing in the perceptual and semantic identification stages (i.e., input stages). Despite the fact that all the input processing stages were completed prior to the presentation of the naming cue, a strong frequency effect was still obtained in this task. These results establish that the lexical frequency effect is independent of variables affecting the input stages of picture naming, and, hence, confirm the lexical frequency effect as a signature effect of lexical access.