Cholinergic deficits selectively boost cortical intratelencephalic control of the striatum in Huntington’s disease

Huntington’s disease (HD) is a progressive, neurodegenerative disease caused by a CAG triplet expansion in the huntingtin gene. Although corticostriatal dysfunction has long been implicated in HD, the determinants and pathway specificity of this pathophysiology remain a matter of speculation. To help fill this gap, the zQ175+/- knockin mouse model of HD was studied using approaches that allowed optogenetic interrogation of intratelencephalic (IT) and pyramidal tract (PT) connections with principal striatal spiny projection neurons (SPNs). These studies revealed that the connectivity of IT, but not PT, neurons with direct and indirect pathway SPNs increased in early symptomatic zQ175+/- HD mice. This enhancement was attributable to reduced inhibitory control of IT terminals by striatal cholinergic interneurons (ChIs). Lowering mutant huntingtin selectively in ChIs with a virally-delivered zinc finger repressor protein normalized striatal acetylcholine release and IT functional connectivity – revealing a novel node in the network underlying corticostriatal pathophysiology in HD.

Biochemical alterations precede neurobehavioral deficits in a novel mouse model of Friedreich ataxia

Friedreich Ataxia (FA) is a rare neuro-cardiodegenerative disease, caused by partial deficiency of frataxin, a mitochondrial protein. This deficiency is caused by the presence of a GAA triplet expansion in the first intron of the frataxin gene or, in some patients, by point mutations. Generating mouse models mimicking FA has been challenging, as this disease is manifested when frataxin levels are below a pathological threshold. In the present work, we have characterized a new mouse model of FA (FXNI151F) based on a pathological point mutation (I154F) present in some FA patients. These mice present very low frataxin levels in all tissues and display neurological deficits resembling those observed in FA patients. We have also observed decreased content of components from OXPHOS complexes I and II, decreased aconitase activity, and alterations in the antioxidant defenses. Remarkably, these biochemical alterations precede the appearance of neurological symptoms and present a different profile in heart and brain or cerebellum. The FXNI151F mouse is an excellent tool for analyzing the consequences of frataxin deficiency in different tissues and for testing new therapies.

Fragile-X-Associated Tremor/Ataxia Syndrome or Alcohol-Induced Cerebellar Degeneration? A Case Report

Fragile-X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that manifests with intention tremor, progressive gait ataxia, and cognitive impairment. The disease is genetically characterized by a premutation of the <i>FMR1</i>gene on the X-chromosome manifesting with a CGG triplet expansion between 55 and 200. Given the phenotypical variety of this disease, diagnosis is frequently delayed. We present and discuss a male patient whose diagnosis of FXTAS was delayed due to his concomitant alcohol abuse.

Analysis of Putative Epigenetic Regulatory Elements in the FXN Genomic Locus

Friedreich’s ataxia (FRDA) is an autosomal recessive disease caused by an abnormally expanded Guanine-Adenine-Adenine (GAA) repeat sequence within the first intron of the frataxin gene (FXN). The molecular mechanisms associated with FRDA are still poorly understood and most studies on FXN gene regulation have been focused on the region around the minimal promoter and the region in which triplet expansion occurs. Nevertheless, since there could be more epigenetic changes involved in the reduced levels of FXN transcripts, the aim of this study was to obtain a more detailed view of the possible regulatory elements by analyzing data from ENCODE and Roadmap consortia databases. This bioinformatic analysis indicated new putative regulatory regions within the FXN genomic locus, including exons, introns, and upstream and downstream regions. Moreover, the region next to the end of intron 4 is of special interest, since the enhancer signals in FRDA-affected tissues are weak or absent in this region, whilst they are strong in the rest of the analyzed tissues. Therefore, these results suggest that there could be a direct relationship between the absence of enhancer sequences in this specific region and their predisposition to be affected in this pathology.

Evidence for genetically determined degeneration of proprioceptive tracts in Friedreich ataxia

ObjectiveTo assess with magnetoencephalography the developmental vs progressive character of the impairment of spinocortical proprioceptive pathways in Friedreich ataxia (FRDA).MethodsNeuromagnetic signals were recorded from 16 right-handed patients with FRDA (9 female patients, mean age 27 years, mean Scale for the Assessment and Rating Of ataxia [SARA] score 22.25) and matched healthy controls while they performed right finger movements either actively or passively. The coupling between movement kinematics (i.e., acceleration) and neuromagnetic signals was assessed by the use of coherence at sensor and source levels. Such coupling, that is, the corticokinematic coherence (CKC), specifically indexes proprioceptive afferent inputs to the contralateral primary sensorimotor (cSM1) cortex. Nonparametric permutations and Spearman rank correlation test were used for statistics.ResultsIn both groups of participants and movement conditions, significant coupling peaked at the cSM1 cortex. Coherence levels were 70% to 75% lower in patients with FRDA than in healthy controls in both movement conditions. In patients with FRDA, coherence levels correlated with genotype alteration (i.e., the size of GAA1 triplet expansion) and the age at symptom onset but not with disease duration or SARA score.ConclusionThis study provides electrophysiologic evidence demonstrating that proprioceptive impairment in FRDA is mostly genetically determined and scarcely progressive after symptom onset. It also positions CKC as a reliable, robust, specific marker of proprioceptive impairment in FRDA.

Cardiomyopathy in Friedreich Ataxia

Friedreich ataxia is the most common human ataxia and results from inadequate production of the frataxin protein, most often the result of a triplet expansion in the nuclear FXN gene. The gene cannot be transcribed to generate the messenger ribonucleic acid for frataxin. Frataxin is an iron-binding protein targeted to the mitochondrial matrix. In its absence, multiple iron-sulfur-dependent proteins in mitochondria and the cytosol lack proper assembly, destroying mitochondrial and nuclear function. Mitochondrial oxidant stress may also participate in ongoing cellular injury. Although progressive and debilitative ataxia is the most prominent clinical finding, hypertrophic cardiomyopathy with heart failure is the most common cause of early death in this disease. There is no cure. In this review the authors cover recent basic and clinical findings regarding the heart in Friedreich ataxia, offer recommendations for clinical management of the cardiomyopathy in this disease, and point out new research directions to advance the field.