Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor

Essential tremor (ET) is a common movement disorder with an estimated prevalence of 5% of the population aged over 65 years. In spite of intensive efforts, the genetic architecture of ET remains unknown. We used a combination of whole-exome sequencing and targeted resequencing in three ET families. In vitro and in vivo experiments in oligodendrocyte precursor cells and zebrafish were performed to test our findings. Whole-exome sequencing revealed a missense mutation in TENM4 segregating in an autosomal-dominant fashion in an ET family. Subsequent targeted resequencing of TENM4 led to the discovery of two novel missense mutations. Not only did these two mutations segregate with ET in two additional families, but we also observed significant over transmission of pathogenic TENM4 alleles across the three families. Consistent with a dominant mode of inheritance, in vitro analysis in oligodendrocyte precursor cells showed that mutant proteins mislocalize. Finally, expression of human mRNA harboring any of three patient mutations in zebrafish embryos induced defects in axon guidance, confirming a dominant-negative mode of action for these mutations. Our genetic and functional data, which is corroborated by the existence of a Tenm4 knockout mouse displaying an ET phenotype, implicates TENM4 in ET. Together with previous studies of TENM4 in model organisms, our studies intimate that processes regulating myelination in the central nervous system and axon guidance might be significant contributors to the genetic burden of this disorde

Safinamide - a unique treatment targeting both dopaminergic and non-dopaminergic systems

Dopaminergic replacement therapies are prescribed widely to improve motor problems in Parkinson's disease (PD). However, as the disease progresses, the response to levodopa (l-dopa) doses becomes shorter and patients experience symptom recurrence at the end of the dose effect. These so-called OFF periods may become refractory to treatment, and may become associated with disabling motor fluctuations or dyskinesias. In addition to dopamine, glutamate excitotoxicity, resulting from disturbance of the homeostatic balance of neurotransmitters and elevated extracellular levels of glutamate, is potentially an important therapeutic target. Safinamide has been investigated in phase III clinical trials as adjunct therapy to l-dopa in mid- to late-stage fluctuating PD. Adding safinamide to l-dopa increases the time patients' symptoms are controlled so-called ON time, without increasing troublesome dyskinesia. Although safinamide has dopaminergic actions, recent data have suggested that the long-term effects of safinamide on dyskinesia are related to safinamide state- and use-dependent inhibition of sodium channels and stimulated glutamate release, rather than reduced dopaminergic stimulation. Safinamide's unique dual mechanism of action makes it a valuable treatment option for fluctuating PD patients

Angiotensin type 1 receptor antagonists protect against alpha-synuclein-induced neuroinflammation and dopaminergic neuron death

The loss of dopaminergic neurons and alpha-synuclein accumulation are major hallmarks of Parkinson's disease (PD), and it has been suggested that a major mechanism of alpha-synuclein toxicity is microglial activation. The lack of animal models that properly reproduce PD, and particularly the underlying synucleinopathy, has hampered the clarification of PD mechanisms and the development of effective therapies. Here, we used neurospecific adeno-associated viral vectors serotype 9 coding for either the wild-type or mutated forms of human alpha-synuclein (WT and SynA53T, respectively) under the control of a synapsin promoter to further induce a marked dopaminergic neuron loss together with an important microglial neuroinflammatory response. Overexpression of neuronal alpha-synuclein led to increased expression of angiotensin type 1 receptors and NADPH oxidase activity, together with a marked increase in the number of OX-6-positive microglial cells and expression of markers of phagocytic activity (CD68) and classical pro-inflammatory/M1 microglial phenotype markers such as inducible nitric oxide synthase, tumor necrosis factor alpha, interleukin-1B, and IL-6. Moreover, a significant decrease in the expression of markers of immunoregulatory/M2 microglial phenotype such as the enzyme arginase-1 was constantly observed. Interestingly, alpha-synuclein-induced changes in microglial phenotype markers and dopaminergic neuron death were inhibited by simultaneous treatment with the angiotensin type 1 blockers candesartan or telmisartan. Our results suggest the repurposing of candesartan and telmisartan as a neuroprotective strategy for PD

Alterations in cerebral white matter and neuropsychology in patients with cirrhosis and falls.

Falls are frequent in patients with cirrhosis but underlying mechanisms are unknown. The aim was to determine the neuropsychological, neurological and brain alterations using magnetic resonance-diffusion tensor imaging (MR-DTI) in cirrhotic patients with falls.Twelve patients with cirrhosis and falls in the previous year were compared to 9 cirrhotic patients without falls. A comprehensive neuropsychological and neurological evaluation of variables that may predispose to falls included: the Mini-Mental State Examination, Psychometric Hepatic Encephalopathy Score (PHES), Parkinson's Disease-Cognitive Rating Scale, specific tests to explore various cognitive domains, Unified Parkinson's Disease Rating Scale to evaluate parkinsonism, scales for ataxia and muscular strength, and electroneurography. High-field MR (3T) including DTI and structural sequences was performed in all patients.The main neuropsychological findings were impairment in PHES (p = 0.03), Parkinson's Disease-Cognitive Rating Scale (p = 0.04) and in executive (p<0.05) and visuospatial-visuoconstructive functions (p<0.05) in patients with falls compared to those without. There were no statistical differences between the two groups in the neurological evaluation or in the visual assessment of MRI. MR-DTI showed alterations in white matter integrity in patients with falls compared to those without falls (p<0.05), with local maxima in the superior longitudinal fasciculus and corticospinal tract. These alterations were independent of PHES as a covariate and correlated with executive dysfunction (p<0.05).With the limitation of the small sample size, our results suggest that patients with cirrhosis and falls present alterations in brain white matter tracts related to executive dysfunction. These alterations are independent of PHES impairment

DTI maps show reduced fractional anisotropy (FA) (A) and increased radial diffusivity (RD) (B) in patients with falls compared to those without falls, including Psychometric Hepatic Encephalopathy Score (PHES) as a covariate.

<p>Results are shown with a Threshold-Free Cluster Enhancement method at p<0.05 corrected. Rows show selected coronal, sagital and axial maxima coordenate slices on a MNI152 brain template image (MNI coordinates). Red voxels have significantly decreased FA values (A), and brown-lightbrown voxels have significantly increased RD values (B). FWE = Family Wise Error; SLF = superior longitudinal fasciculus; CST = corticospinal tract; ILF = inferior longitudinal fasciculus; IFO = inferior frontal-occipital; CC = corpus callosum; CG = cingulate gyrus.</p

Neuromuscular evaluation of patients with falls and patients without falls.

<p>^a MRC: Medical Research Council.</p><p>^b ICARS: International Cooperative Ataxia Rating Scale.</p><p>^c UPDRS-III: Unified Parkinson’s Disease Rating Scale-part III.</p><p>Neuromuscular evaluation of patients with falls and patients without falls.</p

DTI maps show negative fractional anisotropy (FA) (A), and positive mean diffusivity (MD) (B) and radial diffusivity (RD) (C) correlations with Wisconsin Card Sorting Test (WCST) Errors in all cirrhotic patients.

<p>Results are shown with a Threshold-Free Cluster Enhancement method at p<0.05 corrected. Rows show selected coronal, sagital and axial maxima coordenate slices on a MNI152 brain template image (MNI coordinates). Red-yellow voxels are negatively correlated FA values (A), blue-lightblue voxels are positively correlated MD values (B) and brown-lightbrown are positively correlated RD values (C) with WCST Errors scores. FWE = Family Wise Error; SLF = superior longitudinal fasciculus; CST = corticospinal tract; ILF = inferior longitudinal fasciculus; IFO = inferior frontal-occipital; CC = corpus callosum; CG = cingulate gyrus; UF = uncinate fasciculus; HC = hippocampus.</p

Cerebral MRI findings visually assessed in cirrhotic patients with falls and in those without falls.

<p>Cerebral MRI findings visually assessed in cirrhotic patients with falls and in those without falls.</p