133 research outputs found
The End Is the Beginning: Parkinson's Disease in the Light of Brain Imaging
No full textParkinson's disease (PD), the most common neurodegenerative disorder, is characterized by abnormal accumulation of α-synuclein aggregates known as Lewy bodies (LB) and loss of nigrostriatal dopaminergic neurons. Recent neuroimaging studies suggest that in the early phases of PD, synaptic and axonal damage anticipate the onset of a frank neuronal death. Paralleling, even post mortem studies on the brain of affected patients and on animal models support that synapses might represent the primary sites of functional and pathological changes. Indeed, α-synuclein microaggregation and spreading at terminals, by dysregulating the synaptic junction, would block neurotransmitter release, thus triggering a retrograde neurodegenerative process ending with neuronal cell loss by proceeding through the axons. Rather than neurodegeneration, loss of dopaminergic neuronal endings and axons could thus underlie the onset of connectome dysfunction and symptoms in PD and parkinsonisms. However, the manifold biases deriving from the interpretation of human brain imaging data hinder the validation of this hypothesis. Here, we present pivotal evidence supporting that novel comparative brain imaging studies, in patients and experimental models of PD in preliminary stages of disease, could be instrumental for proving whether synaptic endings are the sites where degeneration begins and initiating the factual achievement of disease modifying approaches. The need for such investigations is timely to define an early therapeutic window of intervention to attempt disease halting by terminal and/or axonal healin
Mitochondria and alpha-synuclein: Friends or foes in the pathogenesis of Parkinson's disease?
No full textParkinson’s disease (PD) is a movement disorder characterized by dopaminergic nigrostriatal neuron degeneration and the formation of Lewy bodies (LB), pathological inclusions containing fibrils that are mainly composed of α-synuclein. Dopaminergic neurons, for their intrinsic characteristics, have a high energy demand that relies on the efficiency of the mitochondria respiratory chain. Dysregulations of mitochondria, deriving from alterations of complex I protein or oxidative DNA damage, change the trafficking, size and morphology of these organelles. Of note, these mitochondrial bioenergetics defects have been related to PD. A series of experimental evidence supports that α-synuclein physiological action is relevant for mitochondrial homeostasis, while its pathological aggregation can negatively impinge on mitochondrial function. It thus appears that imbalances in the equilibrium between the reciprocal modulatory action of mitochondria and α-synuclein can contribute to PD onset by inducing neuronal impairment. This review will try to highlight the role of physiological and pathological α-synuclein in the modulation of mitochondrial functions
Repeated administration of (−) sulpiride and SCH 23390 differentially up-regulate D-1 and D-2 dopamine receptor function in rat mesostriatal areas but not in cortical-limbic brain regions
No full textVolume Transmission and the Russian-Doll Organization of Brain Cell Networks: Aspects of Their Integrative Actions.
No full textThe central nervous system (CNS) has been proposed to be formed by functional modules (FMs) that are structurally organized as “Russian dolls”, which form transient assemblies, according to the different integrative tasks that networks within the CNS have to carry out. Integration is achieved by means of communication processes among and within FMs. Two major types of communication processes occur in the CNS, wiring transmission (WT) and volume transmission (VT). WT involves classical synaptic transmission via diffusion of a neurotransmitter across the synaptic cleft, while VT is transmission via a neuroactive substance that is carried by the extracellular and cerebrospinal fluids to distant targets. Recently, evidence has been obtained for the existence of tunneling nanotubes that mediate WT and microvesicles that mediate VT, allowing horizontal transfer of receptors, RNAs, and micro-RNAs.
The recognition and decoding process at the target level involves receptor heteromers (receptor mosaics) that are generated by direct receptor–receptor interactions, as an emergent property of this system. Receptor mosaics allow the integration of incoming information at the plasma membrane level. These new aspects of the structural and functional organization of the CNS open up a new field of investigation in the physiology and pathology of the CNS
Alpha-synuclein modulates NR2B-containing NMDA receptors and decreases their levels after rotenone exposure
No full textAlpha-synuclein (α-syn) is the main protein component of Lewy bodies (LBs), that together with nigrostriatal dopamine neuron loss constitute typical pathological hallmarks of Parkinson's disease (PD). Glutamate N-methyl-d-aspartate receptor (NMDAR) abnormalities, peculiarly involving NR2B-containing NMDAR, have been observed in the brain of PD patients and in several experimental models of the disease. Recent findings, indicating that α-syn can modulate NMDAR trafficking and function, suggest that this protein may be a pivotal regulator of NMDAR activity. Prompted by these evidences, we used fluorescence immunocytochemistry, western blotting and ratiometric Ca(2+) measurements to investigate whether wild type (wt) or C-terminally truncated α-syn can specifically modulate NR2B-containing NMDAR levels, subcellular trafficking and function. In addition, we evaluated whether the exposure of primary cortical neurons to increasing concentrations of rotenone could differentially regulate NR2B levels and cell viability in the presence or in the absence of α-syn. Our results indicate that both wt and C-terminally truncated α-syn negatively modulate NR2B-containing NMDAR levels, membrane translocation and function. Moreover, we found that absence of α-syn abolishes the rotenone-dependent decrease of NR2B levels and reduces neuronal vulnerability in primary cortical neurons. These findings suggest that α-syn can modulate neuronal resilience by regulating NR2B-containing NMDAR, whose specific alterations could connect α-syn pathology to neuronal degeneration in PD
From α-synuclein to synaptic dysfunctions: new insights into the pathophysiology of Parkinson's disease
No full textAlpha-synuclein is a natively unfolded protein playing a key role in the regulation of several neuronal synaptic functions in physiological and pathological conditions. Many studies, over the past years, have shown that it is actively involved in PD pathophysiology. Alpha-synuclein is integrated in a complex network of neuronal processes through the interaction with cytosolic and synaptic proteins. Hence, it is not the sole α-synuclein pathology but its effects on diverse protein partners and specific cellular pathways in the membrane and/or cytosolic districts such as endoplasmic reticulum/Golgi, axonal and synaptic compartments of dopaminergic neurons, that may cause the onset of neuronal cell dysfunction and degeneration which are among the key pathological features of the PD brain. Here we summarize a series of experimental data supporting that α-synuclein aggregation may induce dysfunction and degeneration of synapses via these multiple mechanisms. Taken together, these data add new insights into the complex mechanisms underlying synaptic derangement in PD and other α-synucleinopathies. This article is part of a Special Issue entitled: Brain Integration
Targeting α-Synuclein-Related Synaptic Pathology: Novel Clues for Parkinson’s Disease Therapy
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