A combination of chlorzoxazone and folic acid improves recognition memory, anxiety and depression in SCA3-84Q mice.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is reported to be the most common type of autosomal dominant cerebellar ataxia (ADCA). SCA3 patients suffer from a progressive decline in motor coordination and other disease-associated symptoms. Moreover, recent studies have reported that SCA3 patients also exhibit symptoms of cerebellar cognitive affective syndrome (CCAS).

Memory decline, anxiety and depression in the mouse model of spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant hereditary disorder, caused by an expansion of polyglutamine in the ataxin-3 protein. SCA3 symptoms include progressive motor decline caused by an atrophy of the cerebellum and brainstem. However, it was recently reported that SCA3 patients also suffer from the cerebellar cognitive affective syndrome.

A chlorzoxazone-folic acid combination improves cognitive affective decline in SCA2-58Q mice.

Spinocerebellar ataxia type 2 (SCA2) is a polyglutamine disorder caused by a pathological expansion of CAG repeats in ATXN2 gene. SCA2 is accompanied by cerebellar degeneration and progressive motor decline. Cerebellar Purkinje cells (PCs) seem to be primarily affected in this disorder.

Chronic suppression of STIM1-mediated calcium signaling in Purkinje cells rescues the cerebellar pathology in spinocerebellar ataxia type 2.

Distorted neuronal calcium signaling has been reported in many neurodegenerative disorders, including different types of spinocerebellar ataxias (SCAs). Cerebellar Purkinje cells (PCs) are primarily affected in SCAs and the disturbances in the calcium homeostasis were observed in SCA PCs. Our previous results have revealed that 3,5-dihydroxyphenylglycine (DHPG) induced greater calcium responses in SCA2-58Q PC cultures than in wild type (WT) PC cultures.

Cognitive Decline and Mood Alterations in the Mouse Model of Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is a hereditary disorder, caused by an expansion of polyglutamine in the ataxin-2 protein. Although the mutant protein is expressed throughout all the cell and organ types, the cerebellum is primarily affected. The disease progression is mainly accompanied by a decline in motor functions.

Electrophysiological Studies Support Utility of Positive Modulators of SK Channels for the Treatment of Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2) is an incurable hereditary disorder accompanied by cerebellar degeneration following ataxic symptoms. The causative gene for SCA2 is ATXN2. The ataxin-2 protein is involved in RNA metabolism; the polyQ expansion may interrupt ataxin-2 interaction with its molecular targets, thus representing a loss-of-function mutation.

Structure-Activity Relationship Study of Subtype-Selective Positive Modulators of K2 Channels.

A series of modified -cyclohexyl-2-(3,5-dimethyl-1-pyrazol-1-yl)-6-methylpyrimidin-4-amine (CyPPA) analogues were synthesized by replacing the cyclohexane moiety with different 4-substituted cyclohexane rings, tyrosine analogues, or mono- and dihalophenyl rings and were subsequently studied for their potentiation of K2 channel activity. Among the -benzene--[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine derivatives, halogen decoration at positions 2 and 5 of benzene-substituted 4-pyrimidineamine in compound conferred a ∼10-fold higher potency, while halogen substitution at positions 3 and 4 of benzene-substituted 4-pyrimidineamine in compound conferred a ∼7-fold higher potency on potentiating K2.2a channels, compared to that of the parent template CyPPA.

In vivo analysis of the spontaneous firing of cerebellar Purkinje cells in awake transgenic mice that model spinocerebellar ataxia type 2.

Cerebellar Purkinje cells (PCs) fire spontaneously in a tonic mode, although the precision of this pacemaking activity is disturbed in many abnormal conditions involving cerebellar atrophy, such as many spinocerebellar ataxias (SCAs). In our previous studies we used the single-unit extracellular recording method to analyze spontaneous PC firing in vivo in the anesthetized SCA2-58Q transgenic mice. We realized that PCs from aging SCA2-58Q mice fire much less regularly compared to PCs from their wild type (WT) littermates and this abnormal activity can be reversed with an intraperitoneal (i.

Ataxic Symptoms in Huntington's Disease Transgenic Mouse Model Are Alleviated by Chlorzoxazone.

Huntington's disease (HD) is a hereditary neurodegenerative disease caused by a polyglutamine expansion in the huntingtin protein, Striatum atrophy in HD leads to a progressive disturbance of psychiatric, motor, and cognitive function. Recent studies of HD patients revealed that the degeneration of cerebellum is also observed independently from the striatal atrophy during early HD stage and may contribute to the motor impairment and ataxia observed in HD. Cerebellar Purkinje cells (PCs) are responsible for the proper cerebellar pathways functioning and motor control.

Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2.

The effective therapeutic treatment and the disease-modifying therapy for spinocerebellar ataxia type 2 (SCA2) (a progressive hereditary disease caused by an expansion of polyglutamine in the ataxin-2 protein) is not available yet. At present, only symptomatic treatment and methods of palliative care are prescribed to the patients. Many attempts were made to study the physiological, molecular, and biochemical changes in SCA2 patients and in a variety of the model systems to find new therapeutic targets for SCA2 treatment.

In Vivo Analysis of the Climbing Fiber-Purkinje Cell Circuit in SCA2-58Q Transgenic Mouse Model.

Cerebellar Purkinje cells (PCs) and cerebellar pathways are primarily affected in many autosomal dominant cerebellar ataxias. PCs generate complex spikes (CS) in vivo when activated by climbing fiber (CF) which rise from the inferior olive. In this study, we investigated the functional state of the CF-PC circuitry in the transgenic mouse model of spinocerebellar ataxia type 2 (SCA2), a polyglutamine neurodegenerative genetic disease.

Inositol 1,4,5-trisphosphate receptors and neurodegenerative disorders.

The inositol 1,4,5-trisphosphate receptor (IP R) is an intracellular ion channel that mediates the release of calcium ions from the endoplasmic reticulum. It plays a role in basic biological functions, such as cell division, differentiation, fertilization and cell death, and is involved in developmental processes including learning, memory and behavior. Deregulation of neuronal calcium signaling results in disturbance of cell homeostasis, synaptic loss and dysfunction, eventually leading to cell death.

In vivo analysis of cerebellar Purkinje cell activity in SCA2 transgenic mouse model.

Cerebellar Purkinje cells (PCs) are primarily affected in many spinocerebellar ataxias (SCA). In this study we investigated functional activity of PCs in transgenic mouse model of SCA2, a polyglutamine neurodegenerative hereditary disorder. In our studies we used extracellular single-unit recording method to compare spontaneous activity of PCs in age-matched wild-type mice and SCA2-58Q transgenic mice.