Neuroprotection by Epigenetic Modulation in a Transgenic Model of Multiple System Atrophy

Similar to Parkinson disease, multiple system atrophy (MSA) presents neuropathologically with nigral neuronal loss; however, the hallmark intracellular α-synuclein (αSyn) accumulation in MSA affects typically oligodendrocytes to form glial cytoplasmic inclusions. The underlying pathogenic mechanisms remain unclear. As MSA is predominantly sporadic, epigenetic mechanisms may play a role. We tested the effects of the pan-histone deacetylase inhibitor (HDACi) sodium phenylbutyrate in aged mice overexpressing αSyn under the control of the proteolipid protein promoter (PLP–αSyn) designed to model MSA and characterized by αSyn accumulation in oligodendrocytes and nigral neurodegeneration. HDACi improved motor behavior and survival of nigral neurons in PLP–αSyn mice. Furthermore, HDACi reduced the density of oligodendroglial αSyn aggregates, which correlated with the survival of nigral neurons in PLP–αSyn mice. For the first time, we suggest a role of HDACi in the pathogenesis of MSA-like neurodegeneration and support the future development of selective HDACi for MSA therapy.     

Targeted overexpression of human α-synuclein in oligodendroglia induces lesions linked to MSA -like progressive autonomic failure

Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause manifesting with progressive autonomic failure (AF), cerebellar ataxia and parkinsonism due to neuronal loss in multiple brain areas associated with (oligodendro)glial cytoplasmic α-synuclein (αSYN) inclusions (GCIs). Using proteolipid protein (PLP)-α-synuclein (αSYN) transgenic mice we have previously reported parkinsonian motor deficits triggered by MSA-like αSYN inclusions. We now extend these observations by demonstrating degeneration of brain areas that are closely linked to progressive AF and other non-motor symptoms in MSA, in (PLP)-αSYN transgenic mice as compared to age-matched non-transgenic controls. We show delayed loss of cholinergic neurons in nucleus ambiguus at 12 months of age as well as early neuronal loss in laterodorsal tegmental nucleus, pedunculopontine tegmental nucleus and Onuf's nucleus at 2 months of age associated with αSYN oligodendroglial overexpression. We also report that neuronal loss triggered by MSA-like αSYN inclusions is absent up to 12 months of age in the thoracic intermediolateral cell column suggesting a differential dynamic modulation of αSYN toxicity within the murine autonomic nervous system. Although the spatial and temporal evolution of central autonomic pathology in MSA is unknown our findings corroborate the utility of the (PLP)-αSYN transgenic mouse model as a testbed for the study of oligodendroglial αSYN mediated neurodegeneration replicating both motor and non-motor aspects of MSA.     

Alpha‐synuclein overexpression in mice alters synaptic communication in the corticostriatal pathway

α‐Synuclein (α‐Syn) is a presynaptic protein implicated in Parkinson's disease (PD). Mice overexpressing human wildtype (WT) α‐Syn under the Thy1 promoter show high levels of α‐Syn in cortical and subcortical regions, exhibit progressive sensorimotor anomalies, as well as non‐motor abnormalities and are considered models of pre‐manifest PD as there is little evidence of early loss of dopaminergic (DA) neurons. We used whole‐cell patch clamp recordings from visually identified striatal medium‐sized spiny neurons (MSSNs) in slices from α‐Syn and WT littermate control mice at 35, 90 and 300 days of age to examine corticostriatal synaptic function. MSSNs displayed significant decreases in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in α‐Syn mice at all ages. This difference persisted in the presence of tetrodotoxin, indicating it was independent of action potentials. Stimulation thresholds for evoking EPSCs were significantly higher and responses were smaller in α‐Syn mice. These data suggest a decrease in neurotransmitter release at the corticostriatal synapse. At 90 days the frequency of spontaneous GABA_A receptor‐mediated synaptic currents was decreased in MSSNs but increased in cortical pyramidal neurons. These observations indicate that high levels of expression of α‐Syn alter corticostriatal synaptic function early and they provide evidence for early synaptic dysfunction in a pre‐manifest model of PD. Of importance, these changes are opposite to those found in DA‐depletion models, suggesting that before degeneration of DA neurons in the substantia nigra synaptic adaptations occur at the corticostriatal synapse that may initiate subtle preclinical manifestations. © 2009 Wiley‐Liss, Inc.     

Systemic exosomal siRNA delivery reduced alpha‐synuclein aggregates in brains of transgenic mice

Alpha‐synuclein (α‐Syn) aggregates are the main component of Lewy bodies, which are the characteristic pathological feature in Parkinson's disease (PD) brain. Evidence that α‐Syn aggregation can be propagated between neurones has led to the suggestion that this mechanism is responsible for the stepwise progression of PD pathology. Decreasing α‐Syn expression is predicted to attenuate this process and is thus an attractive approach to delay or halt PD progression. We have used α‐Syn small interfering RNA (siRNA) to reduce total and aggregated α‐Syn levels in mouse brains. To achieve widespread delivery of siRNAs to the brain we have peripherally injected modified exosomes expressing Ravies virus glycoprotein loaded with siRNA. Normal mice were analyzed 3 or 7 days after injection. To evaluate whether this approach can decrease α‐Syn aggregates, we repeated the treatment using transgenic mice expressing the human phosphorylation‐mimic S129D α‐Syn, which exhibits aggregation. In normal mice we detected significantly reduced α‐Syn messenger RNA (mRNA) and protein levels throughout the brain 3 and 7 days after treatment with RVG‐exosomes loaded with siRNA to α‐Syn. In S129D α‐Syn transgenic mice we found a decreased α‐Syn mRNA and protein levels throughout the brain 7 days after injection. This resulted in significant reductions in intraneuronal protein aggregates, including in dopaminergic neurones of the substantia nigra. This study highlights the therapeutic potential of RVG‐exosome delivery of siRNA to delay and reverse brain α‐Syn pathological conditions. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Neuropathology of multiple system atrophy: New thoughts about pathogenesis

Multiple system atrophy (MSA) is a fatal adult‐onset neurodegenerative disorder of uncertain etiology, clinically manifesting with autonomic failure associated with parkinsonism, cerebellar dysfunction, and pyramidal signs in variable combination. The pathological process affects central autonomic, striatonigral, and olivopontocerebellar systems. These show varying degrees of neurodegeneration and underlie the stratification of the heterogenous disorder into MSA‐P and MSA‐C clinical variants, which correlate to the morphologic phenotypes of striatonigral degeneration and olivopontocerebellar atrophy (MSA‐C). The lesions are not limited to these most consistently and severely affected systems but may involve many other parts of the central, peripheral, and autonomic nervous systems, underpinning the multisystem character of MSA. The histological core feature are glial cytoplasmic inclusions (GCIs, Papp‐Lantos bodies) in all types of oligodendroglia that contain aggregates of misfolded α‐Synuclein (α‐Syn). In addition to the ectopic appearance of α‐Syn in oligodendrocytes and other cells, oxidative stress, proteasomal and mitochondrial dysfunction, excitotoxiciy, neuroinflammation, metabolic changes, and energy failure are important contributors to the pathogenesis of MSA, as shown by various neurotoxic and transgenic animal models. Although the basic mechanisms of α‐Syn–triggered neurodegeneration are not completely understood, neuron‐to‐oligodendrocyte transfer of α‐Syn by prion‐like spreading, inducing oligodendroglial and myelin dysfunction associated with chronic neuroinflammation, are suggested finally to lead to a system‐specific pattern of neurodegeneration. © 2014 International Parkinson and Movement Disorder Society     

Rasagiline is neuroprotective in a transgenic model of multiple system atrophy

Rasagiline is a novel selective irreversible monoamine oxidase-B (MAO-B) inhibitor recently introduced for the symptomatic treatment of Parkinson disease. Like other propargylamines rasagiline has also shown neuroprotective effects independent of MAO-B-inhibition in various in vitro and in vivo models. The present study was performed to test the potential of rasagiline as a disease-modifying agent in multiple system atrophy (MSA) using a transgenic mouse model previously described by our group. (PLP)-alpha-synuclein transgenic mice featuring glial cytoplasmic inclusion pathology underwent 3-nitropropionic acid intoxication to model full-blown MSA-like neurodegeneration. Two doses of rasagiline were used (0.8 and 2.5 mg/kg) for a treatment period of 4 weeks. Rasagiline-treated animals were compared to placebo saline-treated mice by evaluation of motor behaviour and neuropathology. Motor behavioural tests including pole test, stride length test and general motor score evaluation showed improvements in motor deficits associated with 2.5 mg/kg rasagiline therapy. Immunohistochemistry and histology showed significant reduction of 3-NP-induced neuronal loss in striatum, substantia nigra pars compacta, cerebellar cortex, pontine nuclei and inferior olives of MSA mice receiving 2.5 mg/kg rasagiline. The results of the study indicate that rasagiline confers neuroprotection in a transgenic mouse model of MSA and may therefore be considered a promising disease-modifying candidate for human MSA.     

Mitochondrial inhibitor 3‐nitroproprionic acid enhances oxidative modification of alpha‐synuclein in a transgenic mouse model of multiple system atrophy

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by autonomic failure, parkinsonism, cerebellar ataxia, and oligodendrocytic accumulation of alpha‐synuclein (αsyn). Oxidative stress has been linked to neuronal death in MSA and the mitochondrial toxin 3‐nitropropionic acid (3NP) is known to enhance the motor deficits and neurodegeneration in transgenic mice models of MSA. However, the effect of 3NP administration on αsyn itself has not been studied. In this context, we examined the neuropathological effects of 3NP administration in αsyn transgenic mice expressing human αsyn (hαsyn) under the control of the myelin basic protein (MBP) promoter and the effect of this administration on posttranslational modifications of αsyn, on levels of total αsyn, and on its solubility. We demonstrate that 3NP administration altered levels of nitrated and oxidized αsyn in the MBP‐hαsyn tg while not affecting global levels of phosphorylated or total αsyn. 3NP administration also exaggerated neurological deficits in the MBP‐hαsyn tg mice, resulting in widespread neuronal degeneration and behavioral impairment. © 2009 Wiley‐Liss, Inc.     

Age‐related motor dysfunction and neuropathology in a transgenic mouse model of multiple system atrophy

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a progressive degeneration of the striatonigral, olivo‐ponto‐cerebellar, and autonomic systems. Glial cytoplasmic inclusions (GCIs) containing alpha‐synuclein represent the hallmark of MSA and are recapitulated in mice expressing alpha‐synuclein in oligodendrocytes. To assess if oligodendroglial expression of human wild‐type alpha‐synuclein in mice (proteolipid promoter, PLP‐SYN) could be associated with age‐related deficits, PLP‐SYN and wild‐type mice were assessed for motor function, brain morphometry, striatal levels of dopamine and metabolites, dopaminergic loss, and distribution of GCIs. PLP‐SYN displayed age‐related impairments on a beam‐traversing task. MRI revealed a significantly smaller brain volume in PLP‐SYN mice at 12 months, which further decreased at 18 months together with increased volume of ventricles and cortical atrophy. The distribution of GCIs was reminiscent of MSA with a high burden in the basal ganglia. Mild dopaminergic cell loss was associated with decreased dopamine turnover at 18 months. These data indicate that PLP‐SYN mice may recapitulate some of the progressive features of MSA and deliver endpoints for the evaluation of therapeutic strategies. Synapse 68:98–106, 2014. © 2013 Wiley Periodicals, Inc.     

Breathing variability and brainstem serotonergic loss in a genetic model of multiple system atrophy

Breathing disorders like sleep apnea, stridor, and dysrythmic breathing are frequent in patients with multiple system atrophy (MSA). These observations have been related to neurodegeneration in several pontomedullary respiratory nuclei and may explain the occurrence of sudden death. In this study, we sought to determine whether these functional and neuropathological characteristics could be replicated in a transgenic model of MSA. Mice expressing human wild‐type α‐synuclein under the control of the proteolipid promoter (PLP‐αSYN) were compared with age‐matched controls. Using whole‐body, unrestrained plethysmography, the following breathing parameters were measured: inspiratory and expiratory times, tidal volume, expiratory volume, peak inspiratory and expiratory flows, and respiratory frequency. For each category, the mean, coefficient of variation, and irregularity score were analyzed. Brains were then processed for stereological cell counts of pontomedullary respiratory nuclei. A significant increase in the coefficient of variation and irregularity score was observed for inspiratory time, tidal volume, and expiratory volume in PLP‐αSYN mice (P < 0.05). Glial cytoplasmic inclusions were found in the medullary raphe of PLP‐αSYN mice, together with a loss of serotonergic immunoreactivity in the raphe obscurus (P < 0.001) and pallidus (P < 0.01). There was a negative correlation between α‐synuclein burden and raphe pallidus cell counts (P < 0.05). There was no significant neuronal loss in the pre‐Botzinger complex. The PLP‐αSYN mouse model replicates the breathing variability and part of the neuronal depletion in pontomedullary respiratory nuclei observed in patients with MSA. Our findings support the use of this model for future candidate drugs in the breathing disorders observed in MSA. © 2014 International Parkinson and Movement Disorder Society     

Review: Multiple system atrophy: emerging targets for interventional therapies

Multiple system atrophy (MSA) is a fatal orphan neurodegenerative disorder that manifests with rapidly progressive autonomic and motor dysfunction. The disease is characterized by the accumulation of α‐synuclein fibrils in oligodendrocytes that form glial cytoplasmic inclusions, a neuropathological hallmark and central player in the pathogenesis of MSA. Here, we summarize the current knowledge on the etiopathogenesis and neuropathology of MSA. We discuss the role of α‐synuclein pathology, microglial activation, oligodendroglial dysfunction and putative cell death mechanisms as candidate therapeutic targets in MSA.     

Viral‐mediated oligodendroglial alpha‐synuclein expression models multiple system atrophy

Background : MSA is a fatal neurodegenerative disorder characterized by a combination of autonomic dysfunction, cerebellar ataxia, and l ‐dopa unresponsive parkinsonism. The hallmark of MSA is the accumulation of α‐synuclein, forming cytoplasmic inclusions in oligodendrocytes. Adeno‐associated viruses allow efficient targeting of disease‐associated genes in selected cellular ensembles and have proven efficient for the neuronal overexpression of α‐synuclein in the substantia nigra in the context of PD. Objectives : We aimed to develop viral‐based models of MSA. Methods : Chimeric viral vectors expressing either human wild‐type α‐synuclein or green fluorescent protein under the control of mouse myelin basic protein were injected in the striatum of rats and monkeys. Rats underwent a longitudinal motor assessment before histopathological analysis at 3 and 6 months. Results : Injection of vectors expressing α‐synuclein in the striatum resulted in >80% oligodendroglial selectivity in rats and >60% in monkeys. Rats developed progressive motor deficits that were l ‐dopa unresponsive when assessed at 6 months. Significant loss of dopaminergic neurons occurred at 3 months, further progressing at 6 months, together with a loss of striatal neurons. Prominent α‐synuclein accumulation, including phosphorylated and proteinase‐K–resistant α‐synuclein, was detected in the striatum and substantia nigra. Conclusions : Viral‐mediated oligodendroglial expression of α‐synuclein allows replicating some of the key features of MSA. This flexible strategy can be used to investigate, in several species, how α‐synuclein accumulation in selected oligodendroglial populations contributes to the pathophysiology of MSA and offers a new framework for preclinical validation of therapeutic strategies. © 2017 International Parkinson and Movement Disorder Society     

Mice expressing the A53T mutant form of human alpha‐synuclein exhibit hyperactivity and reduced anxiety‐like behavior

Genetic mutations associated with α‐synuclein (α‐Syn) are implicated in the pathogenesis of Parkinson's disease (PD). PD is primarily a movement disorder, but patients are known to experience anxiety and other mood disorders. In this study, we examined the effect of the hA53T mutation during development by analyzing the protein expression of norepinephrine (NET), serotonin (SERT), and dopamine (DAT) transporters in addition to assessing locomotor and anxiety‐like behavior. We observed significant decreases in DAT expression at 8 months in transgenic animals compared with normal and younger mice. We used the elevated plus maze, open‐field test, and rotarod apparatus to evaluate wild‐type and hA53T hemizygous mice at 2, 8, and 12 months of age. Our results showed that 12‐month‐old transgenic mice spend more time in the open arms and display a greater number of open entries of the elevated plus maze compared with wild‐type controls and younger mice. Open‐field test results showed that 12‐month‐old mice travel a greater distance overall and travel more in the inner zone than either wild‐type or younger mice. Rotarod testing showed that 8‐ and 12‐month‐old transgenic mice perform better than either wild‐type controls or younger mice. Overall, 8–12‐month‐old transgenic mice showed a trend toward reduced anxiety‐like behavior and increased hyperactivity. These results indicate a possible role of the A53T α‐Syn mutation in anxiety‐like and hyperactive behaviors in a PD mouse model, suggesting that these behaviors might be comorbid with this disease. © 2010 Wiley‐Liss, Inc.     

Evidence for early and progressive ultrasonic vocalization and oromotor deficits in a PINK1 gene knockout rat model of Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disease that leads to a wide range of motor and nonmotor deficits. Specifically, voice and swallow deficits manifest early, are devastating to quality of life, and are difficult to treat with standard medical therapies. The pathological hallmarks of PD include accumulation of the presynaptic protein α‐synuclein (αSyn) as well as degeneration of substantia nigra dopaminergic neurons. However, there is no clear understanding of how or when this pathology contributes to voice and swallow dysfunction in PD. The present study evaluates the effect of loss of function of the phosphatase and tensin homolog‐induced putative kinase 1 gene in rats (PINK1^–/–), a model of autosomal recessive PD in humans, on vocalization, oromotor and limb function, and neurodegenerative pathologies. Behavioral measures include ultrasonic vocalizations, tongue force, biting, and gross motor performance that are assayed at 2, 4, 6, and 8 months of age. Aggregated αSyn and tyrosine hydroxylase immunoreactivity (TH‐ir) were measured at 8 months. We show that, compared with wild‐type controls, PINK1^–/– rats develop 1) early and progressive vocalization and oromotor deficits, 2) reduced TH‐ir in the locus coeruleus that correlates with vocal loudness and tongue force, and 3) αSyn neuropathology in brain regions important for cranial sensorimotor control. This novel approach of characterizing a PINK1^–/– genetic model of PD provides the foundational work required to define behavioral biomarkers for the development of disease‐modifying therapeutics for PD patients. © 2015 Wiley Periodicals, Inc.     

Phosphorylated α‐synuclein immunoreactivity in the posterior pituitary lobe

Parkinson's disease is now recognized as a major form of α‐synucleinopathy involving both the central and peripheral nervous systems. However, no research has focused on the posterior pituitary lobe (PPL), despite the fact that this organ also plays an important role in systemic homeostasis. In the present study, we aimed to distinguish phosphorylated α‐synuclein (pαSyn)‐positive deposits in the PPL, as is observed in Lewy body‐ and non‐Lewy body‐related disorders. PαSyn deposits were immunohistochemically analyzed using formalin‐fixed, paraffin‐embedded PPL specimens obtained from 60 autopsy cases. Among the cases with Lewy body‐related disorders, PPL pαSyn deposits were observed in almost all cases of Parkinson's disease (22/23), and in one case of dementia with Lewy bodies (1/1). On the other hand, only 3/36 cases of non‐Lewy body‐related disorders had pαSyn immunoreactivity in the PPL. The present study confirms the presence of pαSyn‐positive deposits, as demonstrated by high specificity (97.1%) and sensitivity (88.5%), in both Parkinson's disease and dementia with Lewy bodies, suggesting that this finding can be a useful hallmark of Lewy body‐related disorders.     

Videourodynamic and sphincter motor unit potential analyses in Parkinson's disease and multiple system atrophy

OBJECTIVES: Urinary dysfunction is a prominent autonomic feature in Parkinson's disease (PD) and multiple system atrophy (MSA), which is not only troublesome but also a cause of morbidity in these disorders. Recent advances in investigative uroneurology offer a better insight into the underlying pathophysiology and appropriate management for urinary dysfunction. METHODS: twenty one patients with PD (15 men, six women, mean age 64 (49-76), mean disease duration 4 years (1-8 years), median Hoehn and Yahr grade 3 (1-4), all taking 300 mg/day of levodopa (100-500 mg)) and 15 with MSA (eight men, seven women, mean age 59 (48-72), mean disease duration 3 years (0.5-6 years)) were recruited. Videourodynamic and sphincter motor unit potential analyses in the patients with PD and MSA were carried out, looking for distinguishing hallmarks that might be useful in the differential diagnosis of these two diseases. RESULTS: Urinary symptoms were found in 72% of patients with PD and in 100% with MSA. Filling phase abnormalities in the videourodynamic study included detrusor hyperreflexia in 81% of patients with PD and 56% with MSA, and uninhibited external sphincter relaxation in 33% of patients with PD and 33% of those with MSA. However, open bladder neck at the start of filling was not seen in patients with PD but was present in 53% of those with MSA, suggestive of internal sphincter denervation. Sphincter motor unit potential analysis showed neurogenic motor unit potentials in 5% of patients with PD and in 93% of those with MSA, suggestive of external sphincter denervation. On voiding, detrusor-external sphincter dyssynergia was not seen in patients with PD but was present in 47% of those with MSA. Pressure-flow analysis showed that the Abrams-Griffiths number, a grading of urethral obstruction (outflow obstruction >40), in PD (40 in women and 43 in men) was larger than that in MSA (12 in women and 28 in men). Weak detrusor in PD (66% of women and 40% of men) was less common than that in MSA (71% of women and 63% of men). Postmicturition residuals >100 ml were absent in patients with PD but were present in 47% of patients with MSA. CONCLUSION: Patients with PD had less severe urinary dysfunction with little evidence of internal or external sphincter denervation, by contrast with the common findings in MSA. The findings of postmicturition residuals >100 ml, detrusor-external sphincter dyssynergia, open bladder neck at the start of bladder filling, and neurogenic sphincter motor unit potentials are highly suggestive of MSA.     

α‐Synuclein staging in the amygdala of a Parkinson's disease model: cell types involved

Lewy bodies (ubiquitin and α‐synuclein aggregates) can be detected in brain areas in a predictable sequence of six neuropathological stages in Parkinson's disease. Brainstem and olfactory structures are involved in stage 1, whereas the substantia nigra and amygdala are involved in stage 3, prior to cortical spreading. Amygdaloid pathology has been suggested to contribute to non‐motor symptoms such as olfactory dysfunction and emotional impairment. This work analysed the distribution of α‐synuclein at 16, 30, 43 and 56 weeks in the basolateral, central and cortical amygdaloid complexes of A53T transgenic mice. The expression of calbindin, calretinin and somatostatin was compared in control and transgenic animals. Co‐localisation of these markers with α‐synuclein was performed. Triple labeling of calbindin, somatostatin and α‐synuclein was also investigated. Quantification was carried out using an optical dissector, ImageJ software and confocal microscopy. α‐Synuclein‐positive cells were mainly concentrated in the basolateral and cortical amygdaloid complexes with a non‐significant increase over time from 16 to 30–43 weeks and a significant decrease thereafter. The expression of interneuron markers showed a significant decrease with aging in control animals. When comparing these markers between control and transgenic mice, calretinin was moderately decreased, but calbindin and somatostatin were highly reduced, particularly in the cortical amygdaloid complex. α‐Synuclein mostly co‐localised with calbindin and a number of these cells also co‐expressed somatostatin. These data on α‐synucleinopathy staging in the amygdala could help to explain non‐motor symptoms as well as to understand the progression of Parkinson's disease in the brain.     

α-Synuclein decoy peptide protects mice against α-synuclein-induced memory loss

Aims

We previously found that a decoy peptide derived from the C-terminal sequence of α-Synuclein (αSyn) prevents cytotoxic αSyn aggregation caused by fatty acid-binding protein 3 (FABP3) in vitro. In this study, we continued to utilize αSyn-derived peptides to further validate their effects on αSyn neurotoxicity and behavioral impairments in αSyn preformed fibrils (PFFs)-injected mouse model of Parkinson's disease (PD).

Methods

Mice were injected with αSyn PFFs in the bilateral olfactory bulb (OB) and then were subjected to behavioral analysis at 2-week intervals post-injection. Peptides nasal administration was initiated one week after injection. Changes in phosphorylation of αSyn and neuronal damage in the OB were measured using immunostaining at week 4. The effect of peptides on the interaction between αSyn and FABP3 was examined using co-immunoprecipitation.

Results

αSyn PFF-injected mice showed significant memory loss but no motor function impairment. Long-term nasal treatment with peptides effectively prevented memory impairment. In peptide-treated αSyn PFF-injected mice, the peptides entered the OB smoothly through the nasal cavity and were mainly concentrated in neurons in the mitral cell layer, significantly suppressing the excessive phosphorylation of αSyn and reducing the formation of αSyn-FABP3 oligomers, thereby preventing neuronal death. The addition of peptides also blocked the interaction of αSyn and FABP3 at the recombinant protein level, and its effect was strongest at molar concentrations comparable to those of αSyn and FABP3.

Conclusions

Our findings suggest that the αSyn decoy peptide represents a novel therapeutic approach for reducing the accumulation of toxic αSyn-FABP3 oligomers in the brain, thereby preventing the progression of synucleinopathies.     

Targeting α‐synuclein: Therapeutic options

The discovery of the central role of α‐synuclein (αSyn) in the pathogenesis of Parkinson's disease (PD) has powered, in the last decade, the emergence of novel relevant models of this condition based on viral vector‐mediated expression of the disease‐causing protein or inoculation of toxic species of αSyn. Although the development of these powerful tools and models has provided considerable insights into the mechanisms underlying neurodegeneration in PD, it has also been translated into the expansion of the landscape of preclinical therapeutic strategies. Much attention is now brought to the proteotoxic mechanisms induced by αSyn and how to block them using strategies inspired by intrinsic cellular pathways such as the enhancement of cellular clearance by the lysosomal‐autophagic system, through proteasome‐mediated degradation or through immunization. The important effort undertaken by several laboratories and consortia to tackle these issues and identify novel targets warrants great promise for the discovery not only of neuroprotective approaches but also of restorative strategies for PD and other synucleinopathies. In this viewpoint, we summarize the latest advances in this new area of PD research and will discuss promising approaches and ongoing challenges. © 2016 International Parkinson and Movement Disorder Society     

MSA: From basic mechanisms to experimental therapeutics

Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder characterized by rapidly progressive autonomic and motor dysfunction. Pathologically, MSA is mainly characterized by the abnormal accumulation of misfolded α-synuclein in the cytoplasm of oligodendrocytes, which plays a major role in the pathogenesis of the disease. Striatonigral degeneration and olivopontecerebellar atrophy underlie the motor syndrome, while degeneration of autonomic centers defines the autonomic failure in MSA. At present, there is no treatment that can halt or reverse its progression. However, over the last decade several studies in preclinical models and patients have helped to better understand the pathophysiological events underlying MSA. The etiology of this fatal disorder remains unclear and may be multifactorial, caused by a combination of factors which may serve as targets for novel therapeutic approaches. In this review, we summarize the current knowledge about the etiopathogenesis and neuropathology of MSA, its different preclinical models, and the main disease modifying therapies that have been used so far or that are planned for future clinical trials.