Recent Advances in Clinical Trials in Multiple System Atrophy.

PURPOSE OF REVIEW: This review summarizes previous and ongoing neuroprotection trials in multiple system atrophy (MSA), a rare and fatal neurodegenerative disease characterized by parkinsonism, cerebellar, and autonomic dysfunction. It also describes the preclinical therapeutic pipeline and provides some considerations relevant to successfully conducting clinical trials in MSA, i.e., diagnosis, endpoints, and trial design. RECENT FINDINGS: Over 30 compounds have been tested in clinical trials in MSA. While this illustrates a strong treatment pipeline, only two have reached their primary endpoint. Ongoing clinical trials primarily focus on targeting α-synuclein, the neuropathological hallmark of MSA being α-synuclein-bearing glial cytoplasmic inclusions. The mostly negative trial outcomes highlight the importance of better understanding underlying disease mechanisms and improving preclinical models. Together with efforts to refine clinical measurement tools, innovative statistical methods, and developments in biomarker research, this will enhance the design of future neuroprotection trials in MSA and the likelihood of positive outcomes.

Age-related behavioural and striatal dysfunctions in Shank3ΔC/ΔC 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 Shank3ΔC/ΔC mouse model of ASD, and their underlying striatal alterations, at 10 weeks, 20 weeks, and 40 weeks. We highlighted that motor stereotypies worsened at 40 weeks possibly carried by earlier striatal medium spiny neurons (MSN) alterations in GABAergic transmission and morphology. Moreover, we report that 20 weeks could be a critical time-point in the striatal-related ASD physiopathology, and we suggest that MSN alterations may not be the direct consequence of developmental issues, but rather be a consequence of other impairments occurring earlier.

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. METHODS: We lowered brain GRK2 abundance through viral-mediated delivery of a GRK2-specific miRNA and quantified the reversion of a developing or an established insulin-resistant phenotype using the transgenic PLP-SYN mouse model of MSA. RESULTS: Viral vector delivery of a GRK2 miRNA demonstrated a neuroprotective capacity when administered (1) in utero intracerebroventricularly in developing PLP-SYN mice and (2) intrastriatally in adult PLP-SYN mice. Decreased striatal GRK2 levels correlated in both designs with neuroprotection of the substantia nigra dopamine neurons, reduction in high-molecular-weight species of α-synuclein, and reduced insulin resistance. CONCLUSIONS: These data support GRK2 as a potential therapeutic target in MSA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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. Here we show that several ALS-related misfolded proteins including mutants of SOD1 or TDP-43 lead to a significant increase in surface P2X4 receptor density and function in vitro. In addition, we demonstrate in the spinal the cord of SOD1-G93A (SOD1) mice that misfolded SOD1-G93A proteins directly interact with endocytic adaptor protein-2 (AP2); thus, acting as negative competitors for the interaction between AP2 and P2X4, impairing constitutive P2X4 endocytosis. The higher P2X4 surface density was particularly observed in peripheral macrophages of SOD1 mice before the onset and during the progression of ALS symptoms positioning P2X4 as a potential early biomarker for ALS. P2X4 expression was also upregulated in spinal microglia of SOD1 mice during ALS and affect microglial inflammatory responses. Importantly, we report using double transgenic SOD1 mice expressing internalization-defective P2X4mCherryIN knock-in gene or invalidated for the P2X4 gene that P2X4 is instrumental for motor symptoms, ALS progression and survival. This study highlights the role of P2X4 in the pathophysiology of ALS and thus its potential for the development of biomarkers and treatments. We also decipher the molecular mechanism by which misfolded proteins related to ALS impact P2X4 trafficking at early pathological stage in cells expressing-P2X4.

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. A measure of insulin resistance is the amount of the downstream messenger insulin receptor substrate-1 that is phosphorylated at serine residues 312 (IRS-1pS312) or 616 (IRS-1pS616). We assessed IRS-1pS312 and IRS-1pS616 expression in post-mortem brain tissue of PD patients and a preclinical rat model based on viral-mediated expression of A53T mutated human α-synuclein (AAV2/9-h-α-synA53T). METHODS: IRS-1pS312 and IRS-1pS616 staining intensity were determined by immunofluorescence in both neurons and glial cells in the substantia nigra pars compacta (SNc) and putamen of PD patients and controls without known brain disease. We further explored a possible relation between α-synuclein aggregates and brain insulin resistance in PD patients. Both insulin resistance markers were also measured in the SNc and striatum of AAV2/9-h-α-synA53T rats. RESULTS: We found higher IRS-1pS312 staining intensity in nigral dopaminergic neurons and a trend for higher IRS-1pS312 staining intensity in putaminal neurons of PD patients. We observed no differences for IRS-1pS616 staining intensity in neurons or IRS-1pS312 staining intensity in glial cells. IRS-1pS312 showed high co-localisation within the core of nigral Lewy bodies. Like PD patients, AAV2/9-h-α-synA53T rats showed higher IRS-1pS312 staining intensity in the SNc and striatum than controls, whereas IRS-1pS616 was not different between groups. CONCLUSIONS: Our results provide evidence for brain insulin resistance in PD and support the rationale for repurposing anti-diabetic drugs for PD treatment.

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. METHODS: We measured the density of α-synuclein and tau immuno-positive neurons in the substantia nigra, putamen, hippocampal CA1 region, temporal cortex and dentate nucleus of control, MPTP and MPTP+L-DOPA-treated monkeys. Moreover, we also extracted and quantified Triton-X (TX) soluble and insoluble α-synuclein in putamen and hippocampus samples from a separate cohort of control, MPTP and MPTP+L-DOPA-treated monkeys. RESULTS: MPTP-induced α-synuclein accumulation in NHP model of PD was not limited to the substantia nigra but also occurred in the putamen, hippocampal CA1 region and temporal cortex. Tau was increased only in the temporal cortex. Moreover, increased intraneuronal TX insoluble α-synuclein was truncated, but not in the structural form of Lewy bodies. The MPTP-induced increase in α-synuclein levels was abolished in animals having received L-DOPA in all the brain regions, except in the substantia nigra. CONCLUSIONS: Dopamine replacement therapy can dramatically ameliorate α-synuclein pathology in the MPTP NHP model of PD. Therefore, patient's dopaminergic medication should be systematically considered when assessing α-synuclein as a biomarker for diagnosis, monitoring disease progression and response to disease-modifying treatments.

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. In this study, a novel immunocapture technology was developed to isolate blood CNPase-positive, oligodendrocyte-derived enriched microvesicles (OEMVs), followed by fluorescent nanoparticle tracking analysis and assessment of α-syn levels contained within the OEMVs. The results demonstrated that the concentrations of OEMVs were significantly lower in multiple system atrophy patients, compared to Parkinson's disease patients and healthy control subjects. It is also noted that the population of OEMVs involved was mainly in the size range closer to that of exosomes, and that the average α-syn concentrations (per vesicle) contained in these OEMVs were not significantly different among the three groups. The phenomenon of reduced OEMVs was again observed in a transgenic mouse model of multiple system atrophy and in primary oligodendrocyte cultures, and the mechanism involved was likely related, at least in part, to an α-syn-mediated interference in the interaction between syntaxin 4 and VAMP2, leading to the dysfunction of the SNARE complex. These results suggest that reduced OEMVs could be an important mechanism related to pathological α-syn aggregation in oligodendrocytes, and the OEMVs found in peripheral blood could be further explored for their potential as multiple system atrophy biomarkers.

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. The c-Abl inhibitor nilotinib used for the treatment of chronic myeloid leukemia based on data collected in preclinical models of PD might interfere with pathogenic mechanisms that are relevant to PD and dementia with Lewy bodies, which motivated its assessment in an open-label clinical trial in PD and dementia with Lewy bodies patients. The objective of this study was to assess the preclinical efficacy of nilotinib in the specific context of MSA. METHODS: Mice expressing human wild-type α-synuclein in oligodendrocytes received daily injection of nilotinib (1 or 10 mg/kg) over 12 weeks. Postmortem analysis included the assessment of c-Abl activation, α-synuclein burden, and dopaminergic neurodegeneration. RESULTS: α-Synuclein phosphorylated at tyrosine 39 was detected in glial cytoplasmic inclusions in MSA patients. Increased activation of c-Abl and α-synuclein phosphorylation at tyrosine 39 were found in transgenic mice. Despite significant inhibition of c-Abl and associated reduction of α-synuclein phosphorylation at tyrosine 39 by 40%, nilotinib failed to reduce α-synuclein aggregate burden (including phosphorylation at serine 129) in the striatum and cortex or to lessen neurodegeneration in the substantia nigra. CONCLUSIONS: This preclinical study suggests that partial inhibition of c-Abl and reduction of α-synuclein phosphorylation at tyrosine 39 may not be a relevant target for MSA. © 2020 International Parkinson and Movement Disorder Society.

Glucocerebrosidase deficiency in dopaminergic neurons induces microglial activation without neurodegeneration.

Mutations in the GBA1 gene encoding the lysosomal enzyme glucocerebrosidase (GBA1) are important risk factors for Parkinson's disease (PD). In vitro, altered GBA1 activity promotes alpha-synuclein accumulation whereas elevated levels of alpha-synuclein compromise GBA1 function, thus supporting a pathogenic mechanism in PD. However, the mechanisms by which GBA1 deficiency is linked to increased risk of PD remain elusive, partially because of lack of aged models of GBA1 deficiency. As knocking-out GBA1 in the entire brain induces massive neurodegeneration and early death, we generated a mouse model of GBA1 deficiency amenable to investigate the long-term consequences of compromised GBA1 function in dopaminergic neurons. DAT-Cre and GBA1-floxed mice were bred to obtain selective homozygous disruption of GBA1 in midbrain dopamine neurons (DAT-GBA1-KO). Mice were followed for motor function, neuronal survival, alpha-synuclein phosphorylation and glial activation. Susceptibility to nigral viral vector-mediated overexpression of mutated (A53T) alpha-synuclein was assessed. Despite loss of GBA1 and substrate accumulation, DAT-GBA1-KO mice displayed normal motor performances and preserved dopaminergic neurons despite robust microglial activation in the substantia nigra, without accumulation of endogenous alpha-synuclein with respect to wild-type mice. Lysosomal function was only marginally affected. Screening of micro-RNAs linked to the regulation of GBA1, alpha-synuclein or neuroinflammation did not reveal significant alterations. Viral-mediated overexpression of A53T-alpha-synuclein yielded similar neurodegeneration in DAT-GBA1-KO mice and wild-type mice. These results indicate that loss of GBA1 function in mouse dopaminergic neurons is not critical for alpha-synuclein accumulation or neurodegeneration and suggest the involvement of GBA1 deficiency in other cell types as a potential mechanism.

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. Some symptomatic treatments are available, whereas neuroprotection remains an urgent unmet treatment need. In this review, we critically appraise significant developments of the past decade with emphasis on pathogenesis, diagnosis, prognosis, and treatment development. We further discuss unsolved questions and highlight some perspectives. © 2019 International Parkinson and Movement Disorder Society.

Dopamine and addiction: what have we learned from 40 years of research.

Among the neurotransmitters involved in addiction, dopamine (DA) is clearly the best known. The critical role of DA in addiction is supported by converging evidence that has been accumulated in the last 40 years. In the present review, first we describe the dopaminergic system in terms of connectivity, functioning and involvement in reward processes. Second, we describe the functional, structural, and molecular changes induced by drugs within the DA system in terms of neuronal activity, synaptic plasticity and transcriptional and molecular adaptations. Third, we describe how genetic mouse models have helped characterizing the role of DA in addiction. Fourth, we describe the involvement of the DA system in the vulnerability to addiction and the interesting case of addiction DA replacement therapy in Parkinson's disease. Finally, we describe how the DA system has been targeted to treat patients suffering from addiction and the result obtained in clinical settings and we discuss how these different lines of evidence have been instrumental in shaping our understanding of the physiopathology of drug addiction.

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy.

Multiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The cytopathological hallmark of MSA is the accumulation of alpha-synuclein (α-syn) aggregates in affected oligodendrocytes. Several studies point to α-syn oligomerization and aggregation as a mediator of neurotoxicity in synucleinopathies including MSA. C-terminal truncation by the inflammatory protease caspase-1 has recently been implicated in the mechanisms that promote aggregation of α-syn in vitro and in neuronal cell models of α-syn toxicity. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor prodrug VX-765 to mitigate α-syn pathology and to mediate neuroprotection in proteolipid protein α-syn (PLP-SYN) mice, a transgenic mouse model of MSA. PLP-SYN and age-matched wild-type mice were treated for a period of 11 wk with VX-765 or placebo. VX-765 prevented motor deficits in PLP-SYN mice compared with placebo controls. More importantly, VX-765 was able to limit the progressive toxicity of α-syn aggregation by reducing its load in the striatum of PLP-SYN mice. Not only did VX-765 reduce truncated α-syn, but it also decreased its monomeric and oligomeric forms. Finally, VX-765 showed neuroprotective effects by preserving tyrosine hydroxylase-positive neurons in the substantia nigra of PLP-SYN mice. In conclusion, our results suggest that VX-765, a drug that was well tolerated in a 6 wk-long phase II trial in patients with epilepsy, is a promising candidate to achieve disease modification in synucleinopathies by limiting α-syn accumulation.

Deep brain stimulation does not enhance neuroinflammation in multiple system atrophy.

Slowly progressive, levodopa-responsive multiple system atrophy (MSA) may be misdiagnosed as Parkinson's disease (PD). Deep brain stimulation (DBS) is mostly ineffective in these patients and may even worsen the clinical course. Here we assessed whether neuropathological differences between patients with MSA who were treated with DBS of the subthalamic nucleus because of a misleading clinical presentation and typical disease cases may explain the more benign disease course of the former, and also the rapid clinical decline after surgery. The post-mortem assessment included the subthalamic nucleus, the globus pallidus, the thalamus and the putamen in five patients with MSA who received DBS and nine typical disease cases. There was no evidence for distinct neuroinflammatory profiles between both groups that could be related to the surgical procedure or that could explain the rapid clinical progression during DBS. Patients who received deep brain stimulation displayed a higher proportion of α-synuclein bearing neuronal cytoplasmic inclusions in the putamen compared with typical cases, while the number of surviving neurons was not different between groups. Our findings suggest that DBS does not induce neuroinflammatory changes in patients with MSA, at least several years after the surgery. We further hypothesize that the peculiar pattern of α-synuclein pathology may contribute to differences in the clinical phenotype, with a greater proportion of neuronal inclusions in the putamen being associated to a milder, "PD-like" phenotype with sustained levodopa response and slower disease progression.

Motor Impairments Correlate with Social Deficits and Restricted Neuronal Loss in an Environmental Model of Autism.

Background: Motor impairments are amongst the earliest and most consistent signs of autism spectrum disorders but are not used as diagnostic criteria. In addition, the relationship between motor and cognitive impairments and their respective neural substrates remain unknown. Methods: Here, we aimed at determining whether a well-acknowledged animal model of autism spectrum disorders, the valproic acid model, displays motor impairments and whether they may correlate with social deficits and neuronal loss within motor brain areas. For this, pregnant female mice (C57BL/6J) received valproic acid (450 mg/kg) at embryonic day 12.5 and offspring underwent a battery of behavioral analyses before being killed for histological correlates in motor cortex, nigrostriatal pathway, and cerebellum. Results: We show that while valproic acid male mice show both social and motor impairments, female mice only show motor impairments. Prenatal valproic acid exposure induces specific cell loss within the motor cortex and cerebellum and that is of higher magnitude in males than in females. Finally, we demonstrate that motor dysfunction correlates with reduced social behavior and that motor and social deficits both correlate with a loss of Purkinje cells within the Crus I cerebellar area. Conclusions: Our results suggest that motor dysfunction could contribute to social and communication deficits in autism spectrum disorders and that motor and social deficits may share common neuronal substrates in the cerebellum. A systematic assessment of motor function in autism spectrum disorders may potentially help the quantitative diagnosis of autism spectrum disorders and strategies aimed at improving motor behavior may provide a global therapeutic benefit.

Impulse control disorders in Parkinson's disease.

Impulse control disorders (ICD) are frequent side effects of dopamine replacement therapy (DRT) used in Parkinson's disease (PD) with devastating consequences on the patients and caregivers. ICD are behavioural addictions including compulsive gambling, shopping, sexual behaviour, and binge eating that are mainly associated with dopamine D2/D3 agonists. Their management is a real clinical challenge due to the lack of therapeutic alternative. Clinical studies have identified demographic and clinical risk factors for ICD such as younger age at disease onset, male gender, prior history of depression or substance abuse, REM sleep behaviour disorders and higher rate of dyskinesia. PD patients with ICD may also have a specific pattern of dopaminergic denervation in the ventral striatum. Specific evaluation tools have now been designed to better evaluate the severity and impact of ICD in PD. Patients with ICD display altered processing of reward and loss, and decisional bias associated with altered activity in cortical and subcortical areas such as the orbitofrontal cortex, amygdala, insula, anterior cingular cortex, and ventral striatum. Preclinical studies have demonstrated that D2/D3 agonists induce impairments in behavioural processes likely relevant to ICD such as risk-taking behaviour, preference for uncertainty, perseverative responding and sustained drive to engage in gambling-like behaviour. Whether interactions between dopamine denervation and DRT significantly contribute to the pathogenesis of ICD remains poorly understood so far, although features unique to PD have been identified in patients with ICD. Large-scale longitudinal studies are needed to better identify subjects with increased risk to develop ICD and develop therapeutic options.

Insulin resistance and exendin-4 treatment for multiple system atrophy.

See Stayte and Vissel (doi:10.1093/awx064) for a scientific commentary on this article. Multiple system atrophy is a fatal sporadic adult-onset neurodegenerative disorder with no symptomatic or disease-modifying treatment available. The cytopathological hallmark of multiple system atrophy is the accumulation of α-synuclein aggregates in oligodendrocytes, forming glial cytoplasmic inclusions. Impaired insulin/insulin-like growth factor-1 signalling (IGF-1) and insulin resistance (i.e. decreased insulin/IGF-1) have been reported in other neurodegenerative disorders such as Alzheimer's disease. Increasing evidence also suggests impaired insulin/IGF-1 signalling in multiple system atrophy, as corroborated by increased insulin and IGF-1 plasma concentrations in multiple system atrophy patients and reduced IGF-1 brain levels in a transgenic mouse model of multiple system atrophy. We here tested the hypothesis that multiple system atrophy is associated with brain insulin resistance and showed increased expression of the key downstream messenger insulin receptor substrate-1 phosphorylated at serine residue 312 in neurons and oligodendrocytes in the putamen of patients with multiple system atrophy. Furthermore, the expression of insulin receptor substrate 1 (IRS-1) phosphorylated at serine residue 312 was more apparent in inclusion bearing oligodendrocytes in the putamen. By contrast, it was not different between both groups in the temporal cortex, a less vulnerable structure compared to the putamen. These findings suggest that insulin resistance may occur in multiple system atrophy in regions where the neurodegenerative process is most severe and point to a possible relation between α-synuclein aggregates and insulin resistance. We also observed insulin resistance in the striatum of transgenic multiple system atrophy mice and further demonstrate that the glucagon-like peptide-1 analogue exendin-4, a well-tolerated and Federal Drug Agency-approved antidiabetic drug, has positive effects on insulin resistance and monomeric α-synuclein load in the striatum, as well as survival of nigral dopamine neurons. Additionally, plasma levels of exosomal neural-derived IRS-1 phosphorylated at serine residue 307 (corresponding to serine residue 312 in humans) negatively correlated with survival of nigral dopamine neurons in multiple system atrophy mice treated with exendin-4. This finding suggests the potential for developing this peripheral biomarker candidate as an objective outcome measure of target engagement for clinical trials with glucagon-like peptide-1 analogues in multiple system atrophy. In conclusion, our observation of brain insulin resistance in multiple system atrophy patients and transgenic mice together with the beneficial effects of the glucagon-like peptide-1 agonist exendin-4 in transgenic mice paves the way for translating this innovative treatment into a clinical trial.

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.

Multiple System Atrophy - State of the Art.

Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disorder that is characterized by a variable combination of parkinsonism, cerebellar impairment, and autonomic dysfunction. Some symptomatic treatments are available while neuroprotection or disease-modification remain unmet treatment needs. The pathologic hallmark is the accumulation of aggregated alpha-synuclein (α-syn) in oligodendrocytes forming glial cytoplasmic inclusions, which qualifies MSA as synucleinopathy together with Parkinson's disease and dementia with Lewy bodies. Despite progress in our understanding of the pathogenesis of MSA, the origin of α-syn aggregates in oligodendrocytes is still a matter of an ongoing debate. We critically review here studies published in the field over the past 5 years dealing with pathogenesis, genetics, clinical signs, biomarker for improving diagnostic accuracy, and treatment development.

Genetic and pharmacological evidence that endogenous nociceptin/orphanin FQ contributes to dopamine cell loss in Parkinson's disease.

To investigate whether the endogenous neuropeptide nociceptin/orphanin FQ (N/OFQ) contributes to the death of dopamine neurons in Parkinson's disease, we undertook a genetic and a pharmacological approach using NOP receptor knockout (NOP(-/-)) mice, and the selective and potent small molecule NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111). Stereological unbiased methods were used to estimate the total number of dopamine neurons in the substantia nigra of i) NOP(-/-) mice acutely treated with the parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), ii) naïve mice subacutely treated with MPTP, alone or in combination with SB-612111, iii) rats injected with a recombinant adeno-associated viral (AAV) vector overexpressing human mutant p.A53T α-synuclein, treated with vehicle or SB-612111. NOP(-/-) mice showed a 50% greater amount of nigral dopamine neurons spared in response to acute MPTP compared to controls, which was associated with a milder motor impairment. SB-612111, given 4 days after MPTP treatment to mimic the clinical condition, prevented the loss of nigral dopamine neurons and striatal dopaminergic terminals caused by subacute MPTP. SB-612111, administered a week after the AAV injections in a clinically-driven protocol, also increased by 50% both the number of spared nigral dopamine neurons and striatal dopamine terminals, and prevented accompanying motor deficits induced by α-synuclein. We conclude that endogenous N/OFQ contributes to dopamine neuron loss in pathogenic and etiologic models of Parkinson's disease through NOP receptor-mediated mechanisms. NOP receptor antagonists might prove effective as disease-modifying agents in Parkinson's disease, through the rescue of degenerating nigral dopamine neurons and/or the protection of the healthy ones.

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.