Dysfunction of striatal parvalbumin interneurons drives motor stereotypies in Cntnap2-/- mouse model of autism spectrum disorders.

The involvement of parvalbumin (PV) interneurons in autism spectrum disorders (ASD) pathophysiology has been widely described without clearly elucidating how their dysfunctions could lead to ASD symptoms. The Cntnap2-/- mice, an ASD mouse model deficient for a major ASD susceptibility gene, display core ASD symptoms including motor stereotypies, which are directly linked to striatal dysfunction. This study reveals that striatal PV interneurons display hyperexcitability and hyperactivity in Cntnap2-/- mice, along with a reduced response in medium spiny neurons. We also provide evidence for a crucial role of striatal PV interneurons in motor stereotypies by demonstrating that their selective inhibition rescued a wild type-like phenotype. Our study identifies how PV interneuron dysfunctions disrupt striatal circuitry and drive the motor stereotypies in ASD.

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.

Correlation Between Sleep Continuity and Patient-Reported Sleep Quality in Conscious Critically Ill Patients at High Risk of Reintubation: A Pilot Study.

OBJECTIVES: It is well-established that sleep quality of ICU patients is poor, with sleep being highly fragmented by multiple awakenings. These sleep disruptions are associated with poor outcomes such as prolonged weaning duration from mechanical ventilation. Polysomnography can measure sleep continuity, a parameter associated positively with outcomes in patients treated with noninvasive ventilation, but polysomnography is not routinely available in all ICUs, and simple means to assess sleep quality are needed. The Richards-Campbell sleep questionnaire (RCSQ) assesses sleep quality in ICU patients but is difficult to administrate in patients who are not fully awake, and a simpler sleep numeric rating scale (sleep-NRS) has been proposed as an alternative. We here investigated the relationships between sleep continuity and patients-reported sleep quality. DESIGN: Single-center retrospective study. SETTING: Medical ICU of Poitiers University Hospital. PATIENTS: Seventy-two patients were extubated from mechanical ventilation and at high risk of reintubation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed 52 previously recorded polysomnographies in nonsedated and conscious ICU patients. Sleep was recorded the night after extubation. Sleep continuity was measured using an automated scoring algorithm from one electroencephalogram (EEG) channel of the polysomnography. Patient-reported sleep quality was assessed using RCSQ and sleep-NRS. Sleep continuity could be calculated on 45 polysomnographies (age: 68 [58-77], median [25th-75th]) RCSQ (62 [48-72]) and sleep-NRS (6.0 [5.0-7.0]) were obtained in 21 patients and 34 patients, respectively. Our results show a significant correlation between sleep continuity and sleep-NRS (p = 0.0037; ρ = 0.4844; n = 34) but not with RCSQ score (p = 0.6732; ρ = 0.1005; n = 20). CONCLUSION: Sleep continuity correlates with patient-reported sleep quality assessed using sleep-NRS and may capture the refreshing part of sleep. Sleep-NRS can be easily administered in ICU patients. Sleep continuity and sleep-NRS are simple tools that may prove useful to evaluate sleep quality in ICU patients.

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.

Premorbid performances determine the deleterious effects of nigrostriatal degeneration and pramipexole on behavioural flexibility.

Subtle cognitive impairment can occur early in the course of Parkinson's disease (PD) and may manifest under different forms of executive dysfunction such as impaired cognitive flexibility. The precise contribution of nigrostriatal dopaminergic neurodegeneration to these non-motor features of the disease is poorly known. Whether such cognitive impairment associated with the disease process may also predate and contribute to the development of neuropsychiatric side-effects following dopamine replacement therapy remains largely unknown. To address these issues, we investigated the respective contributions of nigrostriatal degeneration and chronic treatment with the dopamine D3-preferring agonist pramipexole on behavioral flexibility in a rat model of PD. Flexible, intermediate and inflexible rats were identified based on baseline assessment of behavioral flexibility using an operant set-shifting task. Nigrostriatal degeneration was induced by bilateral viral-mediated expression of A53T mutated human α-synuclein in the substantia nigra pars compacta and behavioral flexibility was assessed after induction of nigrostriatal degeneration, and during chronic pramipexole treatment. Nigrostriatal degeneration impaired behavioral flexibility in flexible but not in inflexible rats. Pramipexole induced a decrease of behavioral flexibility that was exacerbated in lesioned rats and in the most flexible individuals. Furthermore, the deficits induced by pramipexole in lesioned rats affected different components of the task between flexible and inflexible individuals. This study demonstrates that nigrostriatal degeneration and pramipexole unequally impair behavioral flexibility, suggesting that the susceptibility to develop non-motor impairments upon treatment initiation could primarily depend on premorbid differences in behavioral flexibility.

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.

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.

Age and Gender Differences in Cardiovascular Autonomic Failure in the Transgenic PLP-syn Mouse, a Model of Multiple System Atrophy.

Multiple system atrophy (MSA) is a rare and progressive neurodegenerative disorder. Autonomic failure (AF) is one main clinical feature which has a significant impact on health-related quality of life. The neuropathological hallmark of MSA is the abnormal accumulation of α-synuclein in oligodendrocytes forming glial cytoplasmic inclusions. Only little is known about gender and age differences in AF in MSA. This study was carried out in 6 and 12 months old transgenic PLP-α-syn and WT male and female mice. Heart rate variability (HRV) was assessed both in time, frequential and non-linear domains. Baroreflex sensitivity (BRS) was estimated by the sequence method. Duration of ventricular depolarization and repolarization (QT/QTc intervals) were evaluated from the ECG signals. Three-way ANOVA (genotype x gender x age) with Sidak's method post-hoc was used to analyze data. BRS was significantly changed in PLP-α-syn mice and was age-dependent. QT and QTc intervals were not significantly modified in PLP-α-syn mice. An impaired HRV was observed at 12 months of age in PLP-α-syn female but not in male mice, indicative of cardiovascular AF.

Assessment of Repetitive and Compulsive Behaviors Induced by Pramipexole in Rats: Effect of Alpha-Synuclein-Induced Nigrostriatal Degeneration.

Treatment with dopamine agonists in Parkinson's disease (PD) is associated with debilitating neuropsychiatric side-effects characterized by impulsive and compulsive behaviors. The vulnerability to develop such impairments is thought to involve interactions between individual vulnerability traits, types of antiparkinsonian medications, and the neurodegenerative process. We investigated the effect of the dopamine D3/D2 agonist pramipexole (PPX) and selective nigrostriatal degeneration achieved by viral-mediated expression of alpha-synuclein on the expression of repetitive and compulsive-like behaviors in rats. In a task assessing spontaneous food hoarding behavior, PPX increased the time spent interacting with food pellets at the expense of hoarding. This disruption of hoarding behavior was identical in sham and lesioned rats. In an operant post-training signal attenuation task, the combination of nigrostriatal lesion and PPX decreased the number of completed trials and increased the number of uncompleted trials. The lesion led to an increased compulsive behavior after signal attenuation, and PPX shifted the overall behavioral output towards an increased proportion of compulsive lever-presses. Given the magnitude of the behavioral effects and the lack of strong interaction between PPX and nigral degeneration, these results suggest that extra-nigral pathology may be critical to increase the vulnerability to develop compulsive behaviors following treatment with D3/D2 agonists.

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.

A metabolic biomarker predicts Parkinson's disease at the early stages in patients and animal models.

BackgroundCare management of Parkinson's disease (PD) patients currently remains symptomatic, mainly because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Earlier detection of PD therefore represents a key step for developing therapies able to delay or slow down its progression.MethodsWe investigated metabolic markers in 3 different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 3 cohorts of de novo PD patients and matched controls (n = 129). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics.ResultsOur translational strategy reveals common metabolic dysregulations in serum of the different animal models and PD patients. Some of them were mirrored in the tissue samples, possibly reflecting pathophysiological mechanisms associated with PD development. Interestingly, some metabolic dysregulations appeared before motor symptom emergence and could represent early biomarkers of PD. Finally, we built a composite biomarker with a combination of 6 metabolites. This biomarker discriminated animals mimicking PD from controls, even from the first, nonmotor signs and, very interestingly, also discriminated PD patients from healthy subjects.ConclusionFrom our translational study, which included 3 animal models and 3 de novo PD patient cohorts, we propose a promising biomarker exhibiting a high accuracy for de novo PD diagnosis that may possibly predict early PD development, before motor symptoms appear.FundingFrench National Research Agency (ANR), DOPALCOMP, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes, Association France Parkinson.

Unlucky punches: the vulnerability-stress model for the development of impulse control disorders in Parkinson's disease.

Impulse-control disorders are commonly observed during dopamine-replacement therapy in Parkinson's disease, but the majority of patients seems "immune" to this side effect. Epidemiological evidence suggests that a major risk factor may be a specific difference in the layout of the dopaminergic-reinforcement system, of which the ventral striatum is a central player. A series of imaging studies of the dopaminergic system point toward a presynaptic reduction of dopamine-reuptake transporter density and dopamine synthesis capacity. Here, we review current evidence for a vulnerability-stress model in which a relative reduction of dopaminergic projections to the ventral striatum and concomitant sensitization of postsynaptic neurons represent a predisposing (hypodopaminergic) vulnerability. Stress (hyperdopaminergic) is delivered when dopamine replacement therapy leads to a relative overdosing of the already-sensitized ventral striatum. These alterations are consistent with consecutive changes in reinforcement mechanisms, which stimulate learning from reward and impede learning from punishment, thereby fostering the development of impulse-control disorders. This vulnerability-stress model might also provide important insights into the development of addictions in the non-Parkinsonian population.

Neuropsychiatric and Cognitive Deficits in Parkinson's Disease and Their Modeling in Rodents.

Parkinson's disease (PD) is associated with a large burden of non-motor symptoms including olfactory and autonomic dysfunction, as well as neuropsychiatric (depression, anxiety, apathy) and cognitive disorders (executive dysfunctions, memory and learning impairments). Some of these non-motor symptoms may precede the onset of motor symptoms by several years, and they significantly worsen during the course of the disease. The lack of systematic improvement of these non-motor features by dopamine replacement therapy underlines their multifactorial origin, with an involvement of monoaminergic and cholinergic systems, as well as alpha-synuclein pathology in frontal and limbic cortical circuits. Here we describe mood and neuropsychiatric disorders in PD and review their occurrence in rodent models of PD. Altogether, toxin-based rodent models of PD indicate a significant but non-exclusive contribution of mesencephalic dopaminergic loss in anxiety, apathy, and depressive-like behaviors, as well as in learning and memory deficits. Gene-based models display significant deficits in learning and memory, as well as executive functions, highlighting the contribution of alpha-synuclein pathology to these non-motor deficits. Collectively, neuropsychiatric and cognitive deficits are recapitulated to some extent in rodent models, providing partial but nevertheless useful options to understand the pathophysiology of non-motor symptoms and develop therapeutic options for these debilitating symptoms of PD.

Sleep deprivation reduces vagal tone during an inspiratory endurance task in humans.

STUDY OBJECTIVES: Sleep deprivation alters inspiratory endurance by reducing inspiratory motor output. Vagal tone is involved in exercise endurance. This study aimed to investigate the effect of sleep deprivation on vagal tone adaptation in healthy subjects performing an inspiratory effort. METHODS: Vagal tone was assessed using Heart Rate Variability normalized units of frequency domain component HF (high frequency) before, at the start, and the end of an inspiratory loading trial performed until exhaustion by 16 volunteers after one night of sleep deprivation and one night of normal sleep, where sleep deprivation reduced the inspiratory endurance by half compared to the normal sleep condition (30 min vs 60 min). RESULTS: At rest, heart rate was similar in sleep deprivation and normal sleep conditions. In normal sleep condition, heart rate increased during inspiratory loading task; this increase was greater in sleep deprivation condition. In normal sleep condition, vagal tone increased at the beginning of the trial. This vagal tone increase was absent in sleep deprivation condition. CONCLUSIONS: Sleep deprivation abolished vagal tone response to inspiratory load, possibly contributing to a higher heart rate during the trial and to a reduced inspiratory endurance. CLINICAL TRIAL REGISTRATION: NCT02725190.

Comparison of the expression and toxicity of AAV2/9 carrying the human A53T α-synuclein gene in presence or absence of WPRE.

Woodchuck Hepatitis Virus Post-transcriptional Regulatory Element (WPRE) is thought to enhance transgene expression of target genes delivered by adeno-associated viral (AAV) vectors. This study assessed the protein expression of α-synuclein, phosphorylated α-synuclein at Serine 129, extent of nigrostriatal degeneration as well as subsequent behavioral deficits induced by unilateral intranigral stereotactic injection in male adult C57BL/6J mice of an AAV2/9 expressing A53T human α-synuclein under the control of the synapsin promoter in presence or absence of the WPRE. The presence of WPRE enabled to achieve greater nigrostriatal degeneration and synucleinopathy which was concomitant with worsened forelimb use asymmetry. This work refines a mouse Parkinson's disease model in which anatomo-pathology is related to behavioral deficits.

Mass spectrometry imaging identifies abnormally elevated brain l-DOPA levels and extrastriatal monoaminergic dysregulation in l-DOPA-induced dyskinesia.

l-DOPA treatment for Parkinson's disease frequently leads to dyskinesias, the pathophysiology of which is poorly understood. We used MALDI-MSI to map the distribution of l-DOPA and monoaminergic pathways in brains of dyskinetic and nondyskinetic primates. We report elevated levels of l-DOPA, and its metabolite 3-O-methyldopa, in all measured brain regions of dyskinetic animals and increases in dopamine and metabolites in all regions analyzed except the striatum. In dyskinesia, dopamine levels correlated well with l-DOPA levels in extrastriatal regions, such as hippocampus, amygdala, bed nucleus of the stria terminalis, and cortical areas, but not in the striatum. Our results demonstrate that l-DOPA-induced dyskinesia is linked to a dysregulation of l-DOPA metabolism throughout the brain. The inability of extrastriatal brain areas to regulate the formation of dopamine during l-DOPA treatment introduces the potential of dopamine or even l-DOPA itself to modulate neuronal signaling widely across the brain, resulting in unwanted side effects.

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.

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.