Alpha-synuclein-induced nigrostriatal degeneration and pramipexole treatment disrupt frontostriatal plasticity.

Parkinson's disease is characterized by the degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons, leading to motor and cognitive symptoms. Numerous cellular and molecular adaptations following neurodegeneration or dopamine replacement therapy (DRT) have been described in motor networks but little is known regarding associative basal ganglia loops. This study investigated the contributions of nigrostriatal degeneration and pramipexole (PPX) on neuronal activity in the orbitofrontal cortex (OFC), frontostriatal plasticity, and markers of synaptic plasticity.

Nigral ATP13A2 depletion induces Parkinson's disease-related neurodegeneration in a pilot study in non-human primates.

Lysosomal impairment is strongly implicated in Parkinson's disease (PD). Among the several PD-linked genes, the ATP13A2 gene, associated with the PARK9 locus, encodes a transmembrane lysosomal P5-type ATPase. Mutations in the ATP13A2 gene were primarily identified as the cause of Kufor-Rakeb syndrome (KRS), a juvenile-onset form of PD.

Dysfunction of striatal parvalbumin interneurons drives motor stereotypies in Cntnap2-/- mouse model of autism spectrum disorders.

The involvement of parvalbumin (PV) interneurons in autism spectrum disorders (ASD) pathophysiology has been widely described without clearly elucidating how their dysfunctions could lead to ASD symptoms. The Cntnap2-/- mice, an ASD mouse model deficient for a major ASD susceptibility gene, display core ASD symptoms including motor stereotypies, which are directly linked to striatal dysfunction. This study reveals that striatal PV interneurons display hyperexcitability and hyperactivity in Cntnap2-/- mice, along with a reduced response in medium spiny neurons.

GRK2-Targeted Knockdown as Therapy for Multiple System Atrophy.

Background: Multiple system atrophy (MSA) is a sporadic adult-onset rare neurodegenerative synucleinopathy for which counteracting central nervous system insulin resistance bears the potential of being neuroprotective. G-protein-(heterotrimeric guanine nucleotide-binding protein)-coupled receptor kinase 2 (GRK2) is emerging as a physiologically relevant inhibitor of insulin signaling.

Objectives: We tested whether lowering brain GRK2 abundance may reverse insulin-resistance.

Premorbid performances determine the deleterious effects of nigrostriatal degeneration and pramipexole on behavioural flexibility.

Subtle cognitive impairment can occur early in the course of Parkinson's disease (PD) and may manifest under different forms of executive dysfunction such as impaired cognitive flexibility. The precise contribution of nigrostriatal dopaminergic neurodegeneration to these non-motor features of the disease is poorly known. Whether such cognitive impairment associated with the disease process may also predate and contribute to the development of neuropsychiatric side-effects following dopamine replacement therapy remains largely unknown.

Age-related behavioural and striatal dysfunctions in Shank3 mouse model of autism spectrum disorder.

Autism spectrum disorders (ASDs) are defined as a set of neurodevelopmental disorders and a lifelong condition. In mice, most of the studies focused on the developmental aspects of these diseases. In this paper, we examined the evolution of motor stereotypies through adulthood in the Shank3 mouse model of ASD, and their underlying striatal alterations, at 10 weeks, 20 weeks, and 40 weeks.

Increased surface P2X4 receptors by mutant SOD1 proteins contribute to ALS pathogenesis in SOD1-G93A mice.

Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron (MN) disease characterized by protein misfolding and aggregation leading to cellular degeneration. So far neither biomarker, nor effective treatment has been found. ATP signaling and P2X4 receptors (P2X4) are upregulated in various neurodegenerative diseases.

Age and Gender Differences in Cardiovascular Autonomic Failure in the Transgenic PLP-syn Mouse, a Model of Multiple System Atrophy.

Multiple system atrophy (MSA) is a rare and progressive neurodegenerative disorder. Autonomic failure (AF) is one main clinical feature which has a significant impact on health-related quality of life. The neuropathological hallmark of MSA is the abnormal accumulation of α-synuclein in oligodendrocytes forming glial cytoplasmic inclusions.

Assessment of Repetitive and Compulsive Behaviors Induced by Pramipexole in Rats: Effect of Alpha-Synuclein-Induced Nigrostriatal Degeneration.

Treatment with dopamine agonists in Parkinson's disease (PD) is associated with debilitating neuropsychiatric side-effects characterized by impulsive and compulsive behaviors. The vulnerability to develop such impairments is thought to involve interactions between individual vulnerability traits, types of antiparkinsonian medications, and the neurodegenerative process. We investigated the effect of the dopamine D3/D2 agonist pramipexole (PPX) and selective nigrostriatal degeneration achieved by viral-mediated expression of alpha-synuclein on the expression of repetitive and compulsive-like behaviors in rats.

A metabolic biomarker predicts Parkinson's disease at the early stages in patients and animal models.

BackgroundCare management of Parkinson's disease (PD) patients currently remains symptomatic, mainly because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Earlier detection of PD therefore represents a key step for developing therapies able to delay or slow down its progression.MethodsWe investigated metabolic markers in 3 different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 3 cohorts of de novo PD patients and matched controls (n = 129).

Unlucky punches: the vulnerability-stress model for the development of impulse control disorders in Parkinson's disease.

Impulse-control disorders are commonly observed during dopamine-replacement therapy in Parkinson's disease, but the majority of patients seems "immune" to this side effect. Epidemiological evidence suggests that a major risk factor may be a specific difference in the layout of the dopaminergic-reinforcement system, of which the ventral striatum is a central player. A series of imaging studies of the dopaminergic system point toward a presynaptic reduction of dopamine-reuptake transporter density and dopamine synthesis capacity.

Impaired brain insulin signalling in Parkinson's disease.

Aims: Brain insulin resistance (i.e., decreased insulin/insulin-like growth factor-1 [IGF-1] signalling) may play a role in the pathophysiology of Parkinson's disease (PD), and several anti-diabetic drugs have entred clinical development to evaluate their potential disease-modifying properties in PD.

Neuropsychiatric and Cognitive Deficits in Parkinson's Disease and Their Modeling in Rodents.

Parkinson's disease (PD) is associated with a large burden of non-motor symptoms including olfactory and autonomic dysfunction, as well as neuropsychiatric (depression, anxiety, apathy) and cognitive disorders (executive dysfunctions, memory and learning impairments). Some of these non-motor symptoms may precede the onset of motor symptoms by several years, and they significantly worsen during the course of the disease. The lack of systematic improvement of these non-motor features by dopamine replacement therapy underlines their multifactorial origin, with an involvement of monoaminergic and cholinergic systems, as well as alpha-synuclein pathology in frontal and limbic cortical circuits.

Sleep deprivation reduces vagal tone during an inspiratory endurance task in humans.

Study Objectives: Sleep deprivation alters inspiratory endurance by reducing inspiratory motor output. Vagal tone is involved in exercise endurance. This study aimed to investigate the effect of sleep deprivation on vagal tone adaptation in healthy subjects performing an inspiratory effort.

Comparison of the expression and toxicity of AAV2/9 carrying the human A53T α-synuclein gene in presence or absence of WPRE.

Woodchuck Hepatitis Virus Post-transcriptional Regulatory Element (WPRE) is thought to enhance transgene expression of target genes delivered by adeno-associated viral (AAV) vectors. This study assessed the protein expression of α-synuclein, phosphorylated α-synuclein at Serine 129, extent of nigrostriatal degeneration as well as subsequent behavioral deficits induced by unilateral intranigral stereotactic injection in male adult C57BL/6J mice of an AAV2/9 expressing A53T human α-synuclein under the control of the synapsin promoter in presence or absence of the WPRE. The presence of WPRE enabled to achieve greater nigrostriatal degeneration and synucleinopathy which was concomitant with worsened forelimb use asymmetry.

Mass spectrometry imaging identifies abnormally elevated brain l-DOPA levels and extrastriatal monoaminergic dysregulation in l-DOPA-induced dyskinesia.

l-DOPA treatment for Parkinson's disease frequently leads to dyskinesias, the pathophysiology of which is poorly understood. We used MALDI-MSI to map the distribution of l-DOPA and monoaminergic pathways in brains of dyskinetic and nondyskinetic primates. We report elevated levels of l-DOPA, and its metabolite 3--methyldopa, in all measured brain regions of dyskinetic animals and increases in dopamine and metabolites in all regions analyzed except the striatum.

L-DOPA regulates α-synuclein accumulation in experimental parkinsonism.

Aims: Widespread accumulation of misfolded α-synuclein aggregates is a key feature of Parkinson's disease (PD). Although the pattern and extent of α-synuclein accumulation through PD brains is known, the impact of chronic dopamine-replacement therapy (the gold-standard pharmacological treatment of PD) on the fate of α-synuclein is still unknown. Here, we investigated the distribution and accumulation of α-synuclein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) non-human primate model of PD and determined the effect of chronic L-DOPA treatment on MPTP-induced α-synuclein pathology.

Reduced oligodendrocyte exosome secretion in multiple system atrophy involves SNARE dysfunction.

Transportation of key proteins via extracellular vesicles has been recently implicated in various neurodegenerative disorders, including Parkinson's disease, as a new mechanism of disease spreading and a new source of biomarkers. Extracellular vesicles likely to be derived from the brain can be isolated from peripheral blood and have been reported to contain higher levels of α-synuclein (α-syn) in Parkinson's disease patients. However, very little is known about extracellular vesicles in multiple system atrophy, a disease that, like Parkinson's disease, involves pathological α-syn aggregation, though the process is centred around oligodendrocytes in multiple system atrophy.

Nilotinib Fails to Prevent Synucleinopathy and Cell Loss in a Mouse Model of Multiple System Atrophy.

Background: Multiple system atrophy (MSA) is a rare, untreatable neurodegenerative disorder characterized by accumulation of α-synuclein in oligodendroglial inclusions. As such, MSA is a synucleinopathy along with Parkinson's disease (PD) and dementia with Lewy bodies. Activation of the abelson tyrosine kinase c-Abl leads to phosphorylation of α-synuclein at tyrosine 39, thereby promoting its aggregation and subsequent neurodegeneration.

Multiple System Atrophy: Recent Developments and Future Perspectives.

Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder characterized by a variable combination of parkinsonism, cerebellar impairment, and autonomic dysfunction. The pathologic hallmark is the accumulation of aggregated α-synuclein in oligodendrocytes, forming glial cytoplasmic inclusions, which qualifies MSA as a synucleinopathy together with Parkinson's disease and dementia with Lewy bodies. The underlying pathogenesis is still not well understood.

Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies.

The synucleinopathies Parkinson's disease (PD) and Multiple system atrophy (MSA) - characterized by α-synuclein intracytoplasmic inclusions into, respectively, neurons and oligodendrocytes - are associated with impairment of the autophagy-lysosomal pathways (ALP). Increased expression of the master regulator of ALP, transcription factor EB (TFEB), is hypothesized to promote the clearance of WT α-synuclein and survival of dopaminergic neurons. Here, we explore the efficacy of targeted TFEB overexpression either in neurons or oligodendrocytes to reduce the pathological burden of α-synuclein in a PD rat model and a MSA mouse model.