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The degeneration of mesencephalic dopaminergic neurons that innervate the basal ganglia is responsible for the cardinal motor symptoms of Parkinson's disease (PD). It has been thought that loss of dopaminergic signaling in one basal ganglia region – the striatum – was solely responsible for the network pathophysiology causing PD motor symptoms. While our understanding of dopamine (DA)'s role in modulating striatal circuitry has deepened in recent years, it also has become clear that it acts in other regions of the basal ganglia to influence movement. Underscoring this point, examination of a new progressive mouse model of PD shows that striatal dopamine DA depletion alone is not sufficient to induce parkinsonism and that restoration of extra-striatal DA signaling attenuates parkinsonian motor deficits once they appear. This review summarizes recent advances in the effort to understand basal ganglia circuitry, its modulation by DA, and how its dysfunction drives PD motor symptoms. [ABSTRACT FROM AUTHOR]

The striatum is richly innervated by mesencephalic dopaminergic neurons that modulate a diverse array of cellular and synaptic functions that control goal-directed actions and habits. The loss of this innervation has long been thought to be the principal cause of the cardinal motor symptoms of Parkinson's disease (PD). Moreover, chronic, pharmacological overstimulation of striatal dopamine (DA) receptors is generally viewed as the trigger for levodopa-induced dyskinesia (LID) in late-stage PD patients. Here, we discuss recent advances in our understanding of the relationship between the striatum and DA, particularly as it relates to PD and LID. First, it has become clear that chronic perturbations of DA levels in PD and LID bring about cell type-specific, homeostatic changes in spiny projection neurons (SPNs) that tend to normalize striatal activity. Second, perturbations in DA signaling also bring about non-homeostatic aberrations in synaptic plasticity that contribute to disease symptoms. Third, it has become evident that striatal interneurons are major determinants of network activity and behavior in PD and LID. Finally, recent work examining the activity of SPNs in freely moving animals has revealed that the pathophysiology induced by altered DA signaling is not limited to imbalance in the average spiking in direct and indirect pathways, but involves more nuanced disruptions of neuronal ensemble activity. [ABSTRACT FROM AUTHOR]

The striatum is a hub in the basal ganglia circuitry controlling goal directed actions and habits. The loss of its dopaminergic (DAergic) innervation in Parkinson's disease (PD) disrupts the ability of the two principal striatal projection systems to respond appropriately to cortical and thalamic signals, resulting in the hypokinetic features of the disease. New tools to study brain circuitry have led to significant advances in our understanding of striatal circuits and how they adapt in PD models. This short review summarizes some of these recent studies and the gaps that remain to be filled. [ABSTRACT FROM AUTHOR]

The striatum is densely innervated by mesencephalic dopaminergic neurons that modulate acquisition and vigor of goal-directed actions and habits. This innervation is progressively lost in Parkinson's disease (PD), contributing to the defining movement deficits of the disease. Although boosting dopaminergic signaling with levodopa early in the course of the disease alleviates these deficits, later this strategy leads to the emergence of debilitating dyskinesia. Here, recent advances in our understanding of how striatal cells and circuits adapt to this progressive de-innervation and to levodopa therapy are discussed. First, we discuss how dopamine (DA) depletion triggers cell type-specific, homeostatic changes in spiny projection neurons (SPNs) that tend to normalize striatal activity but also lead to disruption of the synaptic architecture sculpted by experience. Second, we discuss the roles played by cholinergic and nitric oxide-releasing interneurons in these adaptations. Third, we examine recent work in freely moving mice suggesting that alterations in the spatiotemporal dynamics of striatal ensembles contributes to PD movement deficits. Lastly, we discuss recently published evidence from a progressive model of PD suggesting that contrary to the classical model, striatal pathway imbalance is necessary but not sufficient to produce frank parkinsonism. [ABSTRACT FROM AUTHOR]

CalDAG-GEFI (CDGI) is a protein highly enriched in the striatum, particularly in the principal spiny projection neurons (SPNs). CDGI is strongly down-regulated in two hyperkinetic conditions related to striatal dysfunction: Huntington's disease and levodopa-induced dyskinesia in Parkinson's disease. We demonstrate that genetic deletion of CDGI in mice disrupts dendritic, but not somatic, M1 muscarinic receptors (M1Rs) signaling in indirect pathway SPNs. Loss of CDGI reduced temporal integration of excitatory postsynaptic potentials at dendritic glutamatergic synapses and impaired the induction of activity-dependent long-term potentiation. CDGI deletion selectively increased psychostimulant-induced repetitive behaviors, disrupted sequence learning, and eliminated M1R blockade of cocaine self-administration. These findings place CDGI as a major, but previously unrecognized, mediator of cholinergic signaling in the striatum. The effects of CDGI deletion on the self-administration of drugs of abuse and its marked alterations in hyperkinetic extrapyramidal disorders highlight CDGI's therapeutic potential. • CalDAG-GEFI mediates M1 muscarinic receptor dependent plasticity in the striatum. • CDGI mediates dendritic, but not somatic, M1Rs signaling in striatal iSPNs. • CDGI is required for full induction of long-term synaptic potentiation in iSPNs. • Mice lacking CDGI fail to show behavioral plasticity induced by M1R agonists. • Mice lacking CDGI have increased susceptibility to drugs of abuse. [ABSTRACT FROM AUTHOR]

Protocatechuic aldehyde (PAL) has been reported to bind to DJ-1, a key protein involved in Parkinson’s disease (PD), and exerts potential neuroprotective effects via DJ-1 in SH-SY5Y cells. In this study, we investigated the neuroprotective pharmacological effects of PAL against neurotoxin-induced cell and animal models of PD. In cellular models of PD, PAL markedly increased cell viability rates, mitochondrial oxidation-reduction activity and mitochondrial membrane potential, and reduced intracellular ROS levels to prevent neurotoxicity in PC12 cells. In animal models of PD, PAL reduced the apomorphine injection, caused turning in 6-OHDA treated rats, and increased the motor coordination and stride decreases in MPTP treated mice. Meanwhile, in an MPTP mouse model, PAL prevented a decrease of the contents of dopamine (DA) and its metabolites in the striatum and TH-positive dopaminergic neuron loss in the substantia nigra (SN). In addition, PAL increased the protein expression of DJ-1 and reduced the level of α-synuclein in the SN of MPTP lesioned mice. PAL also increased the spine density in hippocampal CA1 neurons. The current study demonstrates that PAL can efficiently protect dopaminergic neurons against neurotoxin injury in vitro and in vivo, and that the potential mechanisms may be related to its effects in increasing DJ-1, decreasing α-synuclein and its growth-promoting effect on spine density. [ABSTRACT FROM AUTHOR]

Levodopa-induced dyskinesia (LID) poses a significant health care challenge for Parkinson's disease (PD) patients. Amantadine is currently the only drug proven to alleviate LID. Although its efficacy in treating LID is widely assumed to be mediated by blockade of N-methyl-D-aspartate (NMDA) glutamate receptors, our experiments demonstrate that at therapeutically relevant concentrations, amantadine preferentially blocks inward-rectifying K+ channel type 2 (Kir2) channels in striatal spiny projection neurons (SPNs) - not NMDA receptors. In so doing, amantadine enhances dendritic integration of excitatory synaptic potentials in SPNs and enhances - not antagonizes - the induction of long-term potentiation (LTP) at excitatory, axospinous synapses. Taken together, our studies suggest that the alleviation of LID in PD patients is mediated by diminishing the disparity in the excitability of direct- and indirect-pathway SPNs in the on state, rather than by disrupting LTP induction. This insight points to a pharmacological approach that could be used to effectively ameliorate LID and improve the quality of life for PD patients. [ABSTRACT FROM AUTHOR]

Abstract: The severe acute respiratory syndrome-coronavirus (SARS-CoV) caused an outbreak of atypical pneumonia in 2003. The SARS-CoV viral genome encodes several proteins which have no homology to proteins in any other coronaviruses, and a number of these proteins have been implicated in viral cytopathies. One such protein is 3a, which is also known as X1, ORF3 and U274. 3a expression is detected in both SARS-CoV infected cultured cells and patients. Among the different functions identified, 3a is a capable of inducing apoptosis. We previously showed that caspase pathways are involved in 3a-induced apoptosis. In this study, we attempted to find out protein domains on 3a that are essential for its pro-apoptotic function. Protein sequence analysis reveals that 3a possesses three major protein signatures, the cysteine-rich, Yxxϕ and diacidic domains. We showed that 3a proteins carrying respective mutations in these protein domains exhibit reduced pro-apoptotic activities, indicating the importance of these domains on 3a''s pro-apoptotic function. It was previously reported that 3a possesses potassium ion channel activity. We further demonstrated that the blockade of 3a''s potassium channel activity abolished caspase-dependent apoptosis. This report provides the first evidence that ion channel activity of 3a is required for its pro-apoptotic function. As ion channel activity has been reported to regulate apoptosis in different pathologic conditions, finding ways to modulate the ion channel activity may offer a new direction toward the inhibition of apoptosis triggered by SARS-CoV. [Copyright &y& Elsevier]