The End Is the Beginning: Parkinson's Disease in the Light of Brain Imaging

Parkinson'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

The Contribution of -Synuclein Spreading to Parkinson’s Disease Synaptopathy

Synaptopathies are diseases with synapse defects as shared pathogenic features, encompassing neurodegenerative disorders such as Parkinson’s disease (PD). In sporadic PD, the most common age-related neurodegenerative movement disorder, nigrostriatal dopaminergic deficits are responsible for the onset of motor symptoms that have been related to -synuclein deposition at synaptic sites. Indeed, -synuclein accumulation can impair synaptic dopamine release and induces the death of nigrostriatal neurons. While in physiological conditions the protein can interact with and modulate synaptic vesicle proteins and membranes, numerous experimental evidences have confirmed that its pathological aggregation can compromise correct neuronal functioning. In addition, recent findings indicate that -synuclein pathology spreads into the brain and can affect the peripheral autonomic and somatic nervous system. Indeed, monomeric, oligomeric, and fibrillary -synuclein can move from cell to cell and can trigger the aggregation of the endogenous protein in recipient neurons. This novel “prion-like” behavior could further contribute to synaptic failure in PD and other synucleinopathies. This review describes the major findings supporting the occurrence of -synuclein pathology propagation in PD and discusses how this phenomenon could induce or contribute to synaptic injury and degeneration

NF-κB in Innate Neuroprotection and Age-Related Neurodegenerative Diseases

NF-κB factors are cardinal transcriptional regulators of inflammation and apoptosis, involved in the brain programing of systemic aging and in brain damage. The composition of NF-κB active dimers and epigenetic mechanisms modulating histone acetylation, finely condition neuronal resilience to brain insults. In stroke models, the activation of NF-κB/c-Rel promotes neuroprotective effects by transcription of specific anti-apoptotic genes. Conversely, aberrant activation of NF-κB/RelA showing reduced level of total acetylation, but site-specific acetylation on lysine 310, triggers the expression of pro-apoptotic genes. Constitutive knockout of c-Rel shatters the resilience of substantia nigra (SN) dopaminergic (DA) neurons to aging and induces a parkinsonian like pathology in mice. c-rel(-/-) mice show increased level of aberrantly acetylated RelA in the basal ganglia, neuroinflammation, accumulation of alpha-synuclein, and iron. Moreover, they develop motor deficits responsive to l-DOPA treatment and associated with loss of DA neurons in the SN. Here, we discuss the effect of unbalanced activation of RelA and c-Rel during aging and propose novel challenges for the development of therapeutic strategies in neurodegenerative diseases

1B/(−)IRE DMT1 Expression during Brain Ischemia Contributes to Cell Death Mediated by NF-κB/RelA Acetylation at Lys310

The molecular mechanisms responsible for increasing iron and neurodegeneration in brain ischemia are an interesting area of research which could open new therapeutic approaches. Previous evidence has shown that activation of nuclear factor kappa B (NF-κB) through RelA acetylation on Lys310 is the prerequisite for p50/RelA-mediated apoptosis in cellular and animal models of brain ischemia. We hypothesized that the increase of iron through a NF-κB-regulated 1B isoform of the divalent metal transporter-1 (1B/DMT1) might contribute to post-ischemic neuronal damage. Both in mice subjected to transient middle cerebral artery occlusion (MCAO) and in neuronally differentiated SK-N-SH cells exposed to oxygen-glucose-deprivation (OGD), 1A/DMT1 was only barely expressed while the 1B/DMT1 without iron-response-element (−IRE) protein and mRNA were early up-regulated. Either OGD or over-expression of 1B/(−)IRE DMT1 isoform significantly increased iron uptake, as detected by total reflection X-ray fluorescence, and iron-dependent cell death. Iron chelation by deferoxamine treatment or (−)IRE DMT1 RNA silencing displayed significant neuroprotection against OGD which concomitantly decreased intracellular iron levels. We found evidence that 1B/(−)IRE DMT1 was a target gene for RelA activation and acetylation on Lys310 residue during ischemia. Chromatin immunoprecipitation analysis of the 1B/DMT1 promoter showed there was increased interaction with RelA and acetylation of H3 histone during OGD exposure of cortical neurons. Over-expression of wild-type RelA increased 1B/DMT1 promoter-luciferase activity, the (−)IRE DMT1 protein, as well as neuronal death. Expression of the acetylation-resistant RelA-K310R construct, which carried a mutation from lysine 310 to arginine, but not the acetyl-mimic mutant RelA-K310Q, down-regulated the 1B/DMT1 promoter, consequently offering neuroprotection. Our data showed that 1B/(−)IRE DMT1 expression and intracellular iron influx are early downstream responses to NF-κB/RelA activation and acetylation during brain ischemia and contribute to the pathogenesis of stroke-induced neuronal damage

NUOVO IMPIEGO TERAPEUTICO PREVENTIVO DELLA SUBUNITA' C-REL DELLA PROTEINA NF-KAPPAB E NUOVO IMPIEGO DI UN ANIMALE TRASGENICO NON UMANO CHE PORTA LA DELEZIONE DEL GENE C-REL (C-REL-/-)

Il brevetto si riferisce all'uso di un animale con delezione del gene NF-kappaB c/Rel come modello di malattia di Parkinson associata a sinucleinopatia e taupatia cerebrale

Role of receptor heterodimers in the development of L-dopa-induced dyskinesias in the 6-hydroxydopamine rat model of Parkinson's disease.

Chronic l-dopa administration is associated with development of dyskinesias. The molecular mechanisms of these side-effects, however, remain elusive. Dopamine (DA) receptors interact with other receptors to form highly organized complexes where their activity is finely tuned by several proteins. The DA D1R forms a heteromeric complex with the NMDA receptor (NMDAR) and this interaction influences the trafficking of both receptors. Using the 6-hydroxydopamine rat model of Parkinson's disease, we report a correlation between the development of l-dopa-induced dyskinesias and changes in synaptic D1R/NMDAR complexe