Improved motor performance in Dyt1 ΔGAG heterozygous knock-in mice by cerebellar Purkinje-cell specific Dyt1 conditional knocking-out

Early-onset generalized torsion dystonia (dystonia 1) is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most patients have a 3-base pair deletion (ΔGAG) in one allele of DYT1, corresponding to a loss of a glutamic acid residue (ΔE) in the C-terminal region of the protein. Functional alterations in basal ganglia circuits and the cerebellum have been reported in dystonia. Pharmacological manipulations or mutations in genes that result in functional alterations of the cerebellum have been reported to have dystonic symptoms and have been used as phenotypic rodent models. Additionally, structural lesions in the abnormal cerebellar circuits, such as cerebellectomy, have therapeutic effects in these models. A previous study has shown that the Dyt1 ΔGAG heterozygous knock-in (KI) mice exhibit motor deficits in the beam-walking test. Both Dyt1 ΔGAG heterozygous knock-in (KI) and Dyt1 Purkinje cell-specific knockout (Dyt1 pKO) mice exhibit dendritic alterations of cerebellar Purkinje cells. Here, Dyt1 pKO mice exhibited significantly less slip numbers in the beam-walking test, suggesting better motor performance than control littermates, and normal gait. Furthermore, Dyt1 ΔGAG KI/Dyt1 pKO double mutant mice exhibited significantly lower numbers of slips than Dyt1 ΔGAG heterozygous KI mice, suggesting Purkinje-cell specific knockout of Dyt1 wild-type (WT) allele in Dyt1 ΔGAG heterozygous KI mice rescued the motor deficits. The results suggest that molecular lesions of torsinA in Purkinje cells by gene therapy or intervening in the signaling pathway downstream of the cerebellar Purkinje cells may rescue motor symptoms in dystonia 1.     

Zika virus-induced acute myelitis and motor deficits in adult interferon αβ/γ receptor knockout mice

Zika virus (ZIKV) has received widespread attention because of its effect on the developing fetus. It is becoming apparent, however, that severe neurological sequelae, such as Guillian-Barrë syndrome (GBS), myelitis, encephalitis, and seizures can occur after infection of adults. This study demonstrates that a contemporary strain of ZIKV can widely infect astrocytes and neurons in the brain and spinal cord of adult, interferon α/β receptor knockout mice (AG129 strain) and cause progressive hindlimb paralysis, as well as severe seizure-like activity during the acute phase of disease. The severity of hindlimb motor deficits correlated with increased numbers of ZIKV-infected lumbosacral spinal motor neurons and decreased numbers of spinal motor neurons. Electrophysiological compound muscle action potential (CMAP) amplitudes in response to stimulation of the lumbosacral spinal cord were reduced when obvious motor deficits were present. ZIKV immunoreactivity was high, intense, and obvious in tissue sections of the brain and spinal cord. Infection in the brain and spinal cord was also associated with astrogliosis as well as T cell and neutrophil infiltration. CMAP and histological analysis indicated that peripheral nerve and muscle functions were intact. Consequently, motor deficits in these circumstances appear to be primarily due to myelitis and possibly encephalitis as opposed to a peripheral neuropathy or a GBS-like syndrome. Thus, acute ZIKV infection of adult AG129 mice may be a useful model for ZIKV-induced myelitis, encephalitis, and seizure activity.     

Abnormal somatosensory temporal discrimination in Parkinson’s disease: Pathophysiological correlates and role in motor control deficits

Objective

The somatosensory temporal discrimination threshold (STDT), defined as the shortest time interval required for two tactile stimuli to be perceived as separate, is longer in patients with Parkinson’s disease (PD). In this review, we discuss STDT findings in healthy subjects and in PD patients and the relationship between altered STDT and motor disturbances.

Altered hippocampal-dependent memory and motor function in neuropilin 2–deficient mice

Semaphorins have an important role in synapse refinement in the mammalian nervous system. The class 3 semaphorin-3F (Sema3F) acting through neuropilin 2/plexin-A3 (Nrp2/PlexA3) holoreceptor complex signals in vivo to restrain apical dendritic spine morphogenesis of cortical pyramidal neurons and hippocampal neurons during postnatal development and mediates excitatory synaptic transmission. Semaphorin signaling has been implicated in the etiology of a number of neurodevelopmental disorders; however, the effects on behavior and mental function of dysregulated Sema3F-Nrp2 signaling have not been fully addressed. The present study is the first behavioral investigation of mice harboring a mutation of the nrp2 gene. Given that loss of Nrp2 signaling alters cortical and hippocampal synaptic organization, we investigated performance of nrp2-deficient mice on learning and sensorimotor function that are known to depend on cortical and hippocampal circuitry. When compared with age-matched controls, nrp2 null mice showed striking impairments in object recognition memory and preference for social novelty. In addition, nrp2^−/− mice displayed impaired motor function in the rotarod test and in observations of grooming behavior. Exploration of novel olfactory sensory stimuli and nociception were unaffected by the loss of Nrp2. Overall, loss of Nrp2 may induce aberrant processing within hippocampal and corticostriatal networks that may contribute to neurodevelopmental disease mechanisms.     

Decreased cocaine motor sensitization and self-administration in mice overexpressing cannabinoid CB? receptors

The potential involvement of the cannabinoid CB? receptors (CB?r) in the adaptive responses induced by cocaine was studied in transgenic mice overexpressing the CB?r (CB?xP) and in wild-type (WT) littermates. For this purpose, the acute and sensitized locomotor responses to cocaine, conditioned place preference, and cocaine intravenous self-administration were evaluated. In addition, we assessed whether CB?r were localized in neurons and/or astrocytes, and whether they colocalized with dopamine D1 and D2 receptors (D1Dr and D2Dr). Dopamine (DA) extracellular levels in the nucleus accumbens (NAcc), and gene expression of tyrosine hydroxylase (TH) and DA transporter (DAT) in the ventral tegmental area (VTA), and μ-opioid and cannabinoid CB? receptors in the NAcc were also studied in both genotypes. CB?xP mice showed decreased motor response to acute administration of cocaine (10-20?mg/kg) and cocaine-induced motor sensitization compared with WT mice. CB?xP mice presented cocaine-induced conditioned place aversion and self-administered less cocaine than WT mice. CB?r were found in neurons and astrocytes and colocalized with D2Dr in the VTA and NAcc. No significant differences in extracellular DA levels in the NAcc were observed between genotypes after cocaine administration. Under baseline conditions, TH and DAT gene expression was higher and μ-opioid receptor gene expression was lower in CB?xP than in WT mice. However, both genotypes showed similar changes in TH and μ-opioid receptor gene expression after cocaine challenge independently of the pretreatment received. Importantly, the cocaine challenge decreased DAT gene expression to a lesser extent in cocaine-pretreated CB?xP than in cocaine-pretreated WT mice. These results revealed that CB?r are involved in cocaine motor responses and cocaine self-administration, suggesting that this receptor could represent a promising target to develop novel treatments for cocaine addiction.     

L-3-n-butylphthalide reduces tau phosphorylation and improves cognitive deficits in AβPP/PS1-Alzheimer's transgenic mice

L-3-n-butylphthalide (L-NBP), an extract from seeds of Apium graveolens Linn (Chinese celery), has been shown to have neuroprotective effects on cerebral ischemic, vascular dementia and amyloid-β (Aβ)-induced animal models by inhibiting oxidative injury, neuronal apoptosis and glial activation, regulating amyloid-β protein precursor (AβPP) processing and reducing Aβ generation. The aim of the present study was to examine the effect of L-NBP on learning and memory in AβPP and presenilin 1 (PS1) double-transgenic AD mouse model (AβPP/PS1) and the mechanisms of L-NBP in reducing Aβ accumulation and tau phosphorylation. Twelve-month old AβPP/PS1 mice were given 15 mg/kg L-NBP by oral gavage for 3 months. L-NBP treatment significantly improved the spatial learning and memory deficits compared to the vehicle-treated AβPP/PS1 mice, whereas L-NBP treatment had no effect on cerebral Aβ plaque deposition and Aβ levels in brain homogenates. However, we found an L-NBP-induced reduction of tau hyperphosphorylation at Ser199, Thr205, Ser396, and Ser404 sites in AβPP/PS1 mice. Additionally, the expressions of cyclin-dependent kinase and glycogen synthase kinase 3β, the most important kinases involved in tau phosphorylation, were markedly decreased by L-NBP treatment. The effects of L-NBP on decreasing tau phosphorylation and kinases activations were further confirmed in neuroblastoma SK-N-SH cells overexpressing wild-type human AβPP695 (SK-N-SH AβPPwt). L-NBP shows promising candidate of multi-target neuronal protective agent for the treatment of Alzheimer's disease.     

Apicidin attenuates memory deficits by reducing the Aβ load in APP/PS1 mice

Aims

Amyloid beta (Aβ) is an important pathological feature of Alzheimer's disease (AD). A disintegrin and metalloproteinase 10 (ADAM10) can reduce the production of toxic Aβ by activating the nonamyloidogenic pathway of amyloid precursor protein (APP). We previously found that apicidin, which is a histone deacetylase (HDAC) inhibitor, can promote the expression of ADAM10 and reduce the production of Aβ in vitro. This study was designed to determine the potential of apicidin treatment to reverse learning and memory impairments in an AD mouse model and the possible correlation of these effects with ADAM10.

Methods

Nine-month-old APP/PS1 mice and C57 mice received intraperitoneal injections of apicidin or vehicle for 2 months. At 11 months of age, we evaluated the memory performance of mice with Morris water maze (MWM) and context fear conditioning tests. The Aβ levels were assessed in mouse brain using the immunohistochemical method and ELISA. The expression of corresponding protein involved in proteolytic processing of APP and the phosphorylation of tau were assessed by Western blotting.

Results

Apicidin reversed the deficits of spatial reference memory and contextual fear memory, attenuated the formation of Aβ-enriched plaques, and decreased the levels of soluble and insoluble Aβ40/42 in APP/PS1 mice. Moreover, apicidin significantly increased the expression of ADAM10, improved the level of sAPPα, and reduced the production of sAPPβ, but did not affect the levels of phosphorylated tau in APP/PS1 mice.

Conclusion

Apicidin significantly improves the AD symptoms of APP/PS1 mice by regulating the expression of ADAM10, which may contribute to decreasing the levels of Aβ rather than decreasing the phosphorylation of tau.     

USP8 protects against lipopolysaccharide-induced cognitive and motor deficits by modulating microglia phenotypes through TLR4/MyD88/NF-κB signaling pathway in mice

Ubiquitin-specific protease 8 (USP8) regulates inflammation in vitro; however, the mechanisms by which USP8 inhibits neuroinflammation and its pathophysiological functions are not completely understood. In this study, we aimed to determine whether USP8 exerts neuroprotective effects in a mouse model of lipopolysaccharide (LPS)-induced cognitive and motor impairment. We commenced intracerebroventricular USP8 administration 7 days prior to i.p. injection of LPS (750 μg/kg). All treatments and behavioral experiments were performed once per day for 7 consecutive days. Behavioral tests and pathological/biochemical assays were performed to evaluate LPS-induced hippocampal damage. USP8 attenuated LPS-induced cognitive and motor impairments in mice. Moreover, USP8 downregulated several pro-inflammatory cytokines [nitric oxide (NO), tumor necrosis factor α (TNF-α), prostaglandin E₂ (PGE₂), and interleukin-1β (IL-1β)] in the serum and brain, and the relevant protein factors [inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2)] in the brain. Furthermore, USP8 upregulated the anti-inflammatory mediators interleukin (IL)-4 and IL-10 in the serum and brain, and promoted a shift from pro-inflammatory to anti-inflammatory microglial phenotypes. The LPS-induced microglial pro-inflammatory phenotype was abolished by TLR4 inhibitor and in TLR4^−/− mice; these effects were similar to those of USP8 treatment. Mechanistically, we found that USP8 increased the expression of neuregulin receptor degradation protein-1 (Nrdp1), potently downregulated the expression of TLR4 and myeloid differentiation primary response protein 88 (MyD88) protein, and inhibited the phosphorylation of IκB kinase (IKK) β and kappa B-alpha (IκBα), thereby reducing nuclear translocation of p65 by inhibiting the activation of the nuclear factor-kappaB (NF-κB) signaling pathway in LPS-induced mice. Our results demonstrated that USP8 exerts protective effects against LPS-induced cognitive and motor deficits in mice by modulating microglial phenotypes via TLR4/MyD88/NF-κB signaling.     

L-alpha-aminoadipic acid restricts dopaminergic neurodegeneration and motor deficits in an inflammatory model of Parkinson’s disease in male rats

Neuroinflammation is a contributory factor underlying the progressive nature of dopaminergic neuronal loss within the substantia nigra (SN) of Parkinson's disease (PD) patients, albeit the role of astrocytes in this process has been relatively unexplored to date. Here, we aimed to investigate the impact of midbrain astrocytic dysfunction in the pathophysiology of intra-nigral lipopolysaccharide (LPS)-induced experimental Parkinsonism in male Wistar rats via simultaneous co-injection of the astrocytic toxin L-alpha-aminoadipic acid (L-AAA). Simultaneous intra-nigral injection of L-AAA attenuated the LPS-induced loss of tyrosine hydroxylase-positive (TH⁺) dopamine neurons in the SNpc and suppressed the affiliated degeneration of TH⁺ dopaminergic nerve terminals in the striatum. L-AAA also repressed LPS-induced nigrostriatal dopamine depletion and provided partial protection against ensuing motor dysfunction. L-AAA abrogated intra-nigral LPS-induced glial fibrillary acidic protein-positive (GFAP⁺) reactive astrogliosis and attenuated the LPS-mediated increases in nigral S100β expression levels in a time-dependent manner, findings which were associated with reduced ionized calcium binding adaptor molecule 1-positive (Iba1⁺) microgliosis, thus indicating a role for reactive astrocytes in sustaining microglial activation at the interface of dopaminergic neuronal loss in response to an immune stimulus. These results indicate that midbrain astrocytic dysfunction restricts the development of dopaminergic neuropathology and motor impairments in rats, highlighting reactive astrocytes as key contributors in inflammatory associated degeneration of the nigrostriatal tract.     

Role of synucleins in traumatic brain injury — An experimental in vitro and in vivo study in mice

Synucleins are small prone to aggregate proteins associated with several neurodegenerative diseases (NDDs), however their role in traumatic brain injury (TBI) is an emerging area of investigation. Using in vitro scratch injury model and in vivo mouse weight-drop model we have found that the injury causes alterations in the expression and localization of synucleins near the damaged area. Before injury, α-synuclein is diffused in the cytoplasm of neurons and γ-synuclein is both in the cytoplasm and nucleus of oligodendrocytes. After the scratch injury of the mixed neuronal and glial culture, α-synuclein forms punctate structures in the cytoplasm of neurons and γ-synuclein is almost completely localized to the nucleus of the oligodendrocytes. Furthermore, the amount of post-translationally modified Met³⁸-oxidized γ-synuclein is increased 3.8 fold 24 h after the scratch. α- and γ-synuclein containing cells increased in the initially cell free scratch zone up to 24 h after the scratch.Intracellular expression and localization of synucleins are also changed in a mouse model of focal closed head injury, using a standardized weight drop device. γ-Synuclein goes from diffuse to punctate staining in a piriform cortex near the amygdala, which may reflect the first steps in the formation of deposits/inclusions. Surprisingly, oxidized γ-synuclein co-localizes with cofilin-actin rods in the thalamus, which are absent in all other regions of the brain. These structures reach their peak amounts 7 days after injury. The changes in γ-synuclein localization are accompanied by injury-induced alterations in the morphology of both astrocytes and neurons.     

Icariin ameliorates memory deficits through regulating brain insulin signaling and glucose transporters in 3×Tg-AD mice

Icariin, a major prenylated flavonoid found in Epimedium spp., is a bioactive constituent of Herba Epimedii and has been shown to exert neuroprotective effects in experimental models of Alzheimer’s disease. In this study, we investigated the neuroprotective mechanism of icariin in an APP/PS1/Tau triple-transgenic mouse model of Alzheimer’s disease. We performed behavioral tests, pathological examination, and western blot assay, and found that memory deficits of the model mice were obviously impr...     

Genetic inactivation of GSK3α rescues spine deficits in Disc1-L100P mutant mice

Disrupted-in-Schizophrenia 1 (DISC1), a strong candidate gene for schizophrenia and other mental disorders, regulates neurodevelopmental processes including neurogenesis, neuronal migration, neurite outgrowth and spine development. Glycogen synthase kinase-3 (GSK3) directly interacts with DISC1 and also plays a role in neurodevelopment. Recently, our group showed that the Disc1-L100P mutant protein has reduced interaction with both GSK3α and β. Genetic and pharmacological inhibition of GSK3 activity rescued behavioral abnormalities in Disc1-L100P mutant mice. However, the cellular mechanisms mediating these effects of GSK3 inhibition in Disc1 mutant mice remain unclear. We sought to investigate the effects of genetic inactivation of GSK3α on frontal cortical neuron morphology in Disc1 L100P mutant mice using Golgi staining. We found a significant decrease in dendritic length and surface area in Disc1-L100P, GSK3α null and L100P/GSK3α double mutants. Dendritic spine density was significantly reduced only in Disc1-L100P and L100P/GSK3α +/- mice when compared to wild-type littermates. There was no difference in dendritic arborization between the various genotypes. No significant rescue in dendritic length and surface area was observed in L100P/GSK3α mutants versus L100P mice, but spine density in L100P/GSK3α mice was comparable to wild-type. Neurite outgrowth and spine development abnormalities induced by Disc1 mutation may be partially corrected through GSK3α inactivation, which also normalizes behavior. However, many of the other dendritic abnormalities in the Disc1-L100P mutant mice were not corrected by GSK3α inactivation, suggesting that only some of the anatomical defects have observable behavioral effects. These findings suggest novel treatment approaches for schizophrenia, and identify a histological read-out for testing other therapeutic interventions.     

TrkB reduction exacerbates Alzheimer's disease-like signaling aberrations and memory deficits without affecting β-amyloidosis in 5XFAD mice

Accumulating evidence shows that brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) significantly decrease early in Alzheimer''s disease (AD). However, it remains unclear whether BDNF/TrkB reductions may be mechanistically involved in the pathogenesis of AD. To address this question, we generated 5XFAD transgenic mice with heterozygous TrkB knockout (TrkB^+/–·5XFAD), and tested the effects of TrkB reduction on AD-like features in this mouse model during an incipient stage that shows only modest amyloid-β (Aβ) pathology and retains normal mnemonic function. TrkB^+/– reduction exacerbated memory declines in 5XFAD mice at 4–5 months of age as assessed by the hippocampus-dependent spontaneous alternation Y-maze task, while the memory performance was not affected in TrkB^+/– mice. Meanwhile, TrkB^+/–·5XFAD mice were normal in nest building, a widely used measure for social behavior, suggesting the memory-specific aggravation of AD-associated behavioral impairments. We found no difference between TrkB^+/–·5XFAD and 5XFAD control mice in cerebral plaque loads, Aβ concentrations including total Aβ42 and soluble oligomers and β-amyloidogenic processing of amyloid precursor protein. Interestingly, reductions in hippocampal expression of AMPA/NMDA glutamate receptor subunits as well as impaired signaling pathways downstream to TrkB such as CREB (cAMP response element-binding protein) and Akt/GSK-3β (glycogen synthase kinase-3β) were observed in TrkB^+/–·5XFAD mice but not in 5XFAD mice. Among these signaling aberrations, only Akt/GSK-3β dysfunction occurred in TrkB^+/– mice, while others were synergistic consequences between TrkB reduction and subthreshold levels of Aβ in TrkB^+/–·5XFAD mice. Collectively, our results indicate that reduced TrkB does not affect β-amyloidosis but exacerbates the manifestation of hippocampal mnemonic and signaling dysfunctions in early AD.     

Sodium selenate specifically activates PP2A phosphatase,dephosphorylates tau and reverses memory deficits in an Alzheimer’s disease model

Neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein are a hallmark of Alzheimer’s disease (AD) and related tauopathies. Tau hyperphosphorylation is thought to promote aggregation with subsequent tangle formation. Reducing tau phosphorylation by boosting the activity of the key phosphatase/s that mediate dephosphorylation of tau could be a viable clinical strategy in AD. One of the key phosphatases implicated in regulating tau protein phosphorylation is the serine–threonine phosphatase PP2A. We have determined that sodium selenate can act as a specific agonist for PP2A, significantly boosting phosphatase activity. Acute treatment of either neuroblastoma cells or normal aged mice with sodium selenate rapidly reduced tau protein phosphorylation. Sodium selenate-treated transgenic TAU441 mice had significantly lower levels of phospho- and total tau levels in the hippocampus and amygdala compared with controls and exhibited significantly improved spatial learning and memory on the Morris Water Maze task. Sodium selenate is a specific activator of PP2A with excellent oral bioavailability, and favourable central nervous system penetrating properties. Clinical studies in patients with AD are envisaged in the near future.     

Neural correlates of speech and limb motor timing deficits revealed by aberrant beta band desynchronization in Parkinson’s disease

ObjectiveWe used a classical motor reaction time paradigm to examine the effects of Parkinson’s disease (PD) on the mechanisms of speech production and upper limb movement.MethodsElectro-encephalography (EEG) signals were recorded in PD and control groups during speech vowel production and button press tasks in response to temporally predictable and unpredictable visual stimuli.ResultsMotor reaction times were slower in PD vs. control group independent of stimulus timing and movement modality. This effect was accompanied by stronger desynchronizations of low beta (13–18 Hz) and high beta (18–25 Hz) band neural oscillations in PD vs. control prior to the onset of speech and hand movement. In addition, pre-movement desynchronization of beta band oscillations were correlated with motor reaction time in control subjects with faster responses associated with weaker beta band desynchronizations during the planning phase of movement. However, no such effect was found in the PD group.ConclusionsWe suggest that the aberrant pattern of beta band desynchronization is a neural correlate of speech and upper limb motor timing deficits as a result of cortico-striatal pathology in PD.SignificanceThese findings motivate interventions targeted toward normalizing beta band activities for improving speech and upper limb movement timing in PD.     

Inhibition and attentional control in pedophilic child sexual offenders – An event-related potential study

Objective

Impaired response inhibition might play a role in child sexual offences. Recording of event-related potentials (ERPs) can help to clarify whether child sexual offenders (CSOs) show an altered processing of stop signals and commission errors.

Exercise improves motor deficits and alters striatal GFAP expression in a 6-OHDA-induced rat model of Parkinson’s disease

Astrocytic changes have been demonstrated in several neurodegenerative diseases, showing that these cells play an important role in functional recovery/maintenance against brain damage. Physical exercise is known to contribute to this process; however, the cellular mechanisms involved are not fully understood. This study investigated the effects of physical exercise on motor deficits and the expression of glial fibrillary acidic protein (GFAP) in a model of Parkinson's disease (PD). Rats were divided into four groups: sham sedentary (SS) and sham trained (ST); lesioned sedentary (LS) and lesioned trained (LT). 6-OHDA was infused unilaterally into the medial forebrain bundle. Behavioral tasks were applied to evaluate motor abilities. Tyrosine hydroxylase (TH-in substantia nigra) and GFAP (in striatum) immunoreactivities (ir) were semi-quantified using optical density. The animals submitted to treadmill training completed fewer pharmacological-induced rotations when compared with sedentary animals and they also showed ameliorated motor impairments. Interestingly, although no change in TH-ir, the exercise led to restored striatal GFAP expression in the LT group while there was no effect in the ST group. This study is the first study to show data indicating the recovery of GFAP expression post-exercise in this model and further research is necessary to determine the precise action mechanisms of exercise on astrocytes in the PD.     

Nigrostriatal overabundance of α-synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activity

α-Synuclein (α-syn) is a presynaptic protein present at most nerve terminals, but its function remains largely unknown. The familial forms of Parkinson's disease associated with multiplications of the α-syn gene locus indicate that overabundance of this protein might have a detrimental effect on dopaminergic transmission. To investigate this hypothesis, we use adeno-associated viral (AAV) vectors to overexpress human α-syn in the rat substantia nigra. Moderate overexpression of either wild-type (WT) or A30P α-syn differs in the motor phenotypes induced, with only the WT form generating hemiparkinsonian impairments. Wild-type α-syn causes a reduction of dopamine release in the striatum that exceeds the loss of dopaminergic neurons, axonal fibers, and the reduction in total dopamine. At the ultrastructural level, the reduced dopamine release corresponds to a decreased density of dopaminergic vesicles and synaptic contacts in striatal terminals. Interestingly, the membrane-binding-deficient A30P mutant does neither notably reduce dopamine release nor it cause ultrastructural changes in dopaminergic axons, showing that α-syn's membrane-binding properties are critically involved in the presynaptic defects. To further determine if the affinity of the protein for membranes determines the extent of motor defects, we compare three forms of α-syn in conditions leading to pronounced degeneration. While membrane-binding α-syns (wild-type and A53T) induce severe motor impairments, an N-terminal deleted form with attenuated affinity for membranes is inefficient in inducing motor defects. Overall, these results demonstrate that α-syn overabundance is detrimental to dopamine neurotransmission at early stages of the degeneration of nigrostriatal dopaminergic axons.     

Abnormal premotor–motor interaction in heterozygous Parkin- and Pink1 mutation carriers

Objectives

Mutations in the Parkin and PINK1 gene account for the majority of autosomal recessive early-onset Parkinson cases. There is increasing evidence that clinically asymptomatic subjects with single heterozygous mutations have a latent nigrostriatal dopaminergic deficit and could be taken as in vivo model of pre-symptomatic phase of Parkinsonism.