Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4.

Amyotrophic lateral sclerosis (ALS) is a heterogenous neurodegenerative disorder that affects motor neurons and voluntary muscle control1. ALS heterogeneity includes the age of manifestation, the rate of progression and the anatomical sites of symptom onset. Disease-causing mutations in specific genes have been identified and define different subtypes of ALS1. Although several ALS-associated genes have been shown to affect immune functions2, whether specific immune features account for ALS heterogeneity is poorly understood. Amyotrophic lateral sclerosis-4 (ALS4) is characterized by juvenile onset and slow progression3. Patients with ALS4 show motor difficulties by the time that they are in their thirties, and most of them require devices to assist with walking by their fifties. ALS4 is caused by mutations in the senataxin gene (SETX). Here, using Setx knock-in mice that carry the ALS4-causative L389S mutation, we describe an immunological signature that consists of clonally expanded, terminally differentiated effector memory (TEMRA) CD8 T cells in the central nervous system and the blood of knock-in mice. Increased frequencies of antigen-specific CD8 T cells in knock-in mice mirror the progression of motor neuron disease and correlate with anti-glioma immunity. Furthermore, bone marrow transplantation experiments indicate that the immune system has a key role in ALS4 neurodegeneration. In patients with ALS4, clonally expanded TEMRA CD8 T cells circulate in the peripheral blood. Our results provide evidence of an antigen-specific CD8 T cell response in ALS4, which could be used to unravel disease mechanisms and as a potential biomarker of disease state.

Molecular mechanism of prion-like tau-induced neurodegeneration.

INTRODUCTION: Accumulation of hyperphosphorylated tau and the disruption of microtubules are correlated with synaptic loss and pathology of Alzheimer's disease (AD). Impaired cognitive function and pathology of AD is correlated with this lesion. This review looks at the mechanism of neurodegeneration, the prion-like behavior of tau in its interaction with normal MAPs in correlation with tau hyperphosphorylation. METHODS: We reviewed our work in the field as well as current literature that pertains to tau phosphorylation and the biological effects. RESULTS: Hyperphosphorylation of tau in AD, in vitro, in cells, or in animal models converts this protein into a prion-like protein that is able to propagate the altered conformation. DISCUSSION: These findings suggest that phosphorylation of tau is a critical event in neurodegeneration. The combination of phosphorylation sites can generate a gain of toxic function for tau. The mechanism of tau toxicity might involve not only the microtubule system but also interference with other cellular compartments such as the nucleus and the actin cytoskeleton.

Tau-induced neurodegeneration: mechanisms and targets.

The accumulation of hyperphosphorylated tau is a common feature of several dementias. Tau is one of the brain microtubule-associated proteins. Here we discuss tau's functions in microtubule assembly and stabilization and with regard to its interactions with other proteins. We describe and analyze important post-translational modifications: hyperphosphorylation, ubiquitination, glycation, glycosylation, nitration, polyamination, proteolysis, acetylation, and methylation. We discuss how these post-translational modifications can alter tau's biological function. We analyze the role of mitochondrial health in neurodegeneration. We propose that microtubules could be a therapeutic target and review different approaches. Finally, we consider whether tau accumulation or its conformational change is related to tau-induced neurodegeneration, and propose a mechanism of neurodegeneration.

Expression of Alzheimer-like pathological human tau induces a behavioral motor and olfactory learning deficit in Drosophila melanogaster.

A key characteristic of Alzheimer's disease and other tauopathies is the progressive accumulation of neurofibrillary tangles mainly composed of hyperphosphorylated tau protein. In the present study, we use transgenic Drosophila melanogaster as a model to analyze in vivo the effect of expressing pseudophosphorylated tau (S199E/T212E/T231E/S262E tau) on pathological human tau (PH-tau) and on the FTDP-17 mutant R406W (PH-tauR406W). We used two different inducers that produced different levels of tau expression. The expression of these forms of tau did not significantly affect the lifespan of the flies. Flies expressing PH-tau displayed a clear locomotor dysfunction compared to those expressing normal tau regardless of the level of expression. At lower level of expression, this pathological phenotype was found to be age-dependent. At 35 days old, PH-tau flies showed the strongest locomotor impairment compare to flies expressing human tau or control flies (46%, 18% and 18% of flies remained on the bottom of the vials, respectively). At higher levels of expression, PH-tau flies showed these defects at seven days of age and the dysfunction also became significant for flies expressing tauR406W and PH-tauR406W. Whole brain immunochemistry analysis revealed that PH-tau as well as PH-tauR406W appeared to have abnormal mushroom body structures, critical structures involved in olfactory learning and memory in Drosophila. Severe olfactory learning deficits were induced by the expression of PH-tau. Taken together, our findings demonstrate that PH-tau induced a toxic effect in Drosophila, as flies develop both an abnormal motor deficit, associated with disruption of the mushroom body neurons, and impaired olfactory learning.