New Developments in Genetic rat models of Parkinson's Disease

Preclinical research on Parkinson's disease has relied heavily on mouse and rat animal models. Initially, PD animal models were generated primarily by chemical neurotoxins that induce acute loss of dopaminergic neurons in the substantia nigra. On the discovery of genetic mutations causally linked to PD, mice were used more than rats to generate laboratory animals bearing PD‐linked mutations because mutagenesis was more difficult in rats. Recent advances in technology for mammalian genome engineering and optimization of viral expression vectors have increased the use of genetic rat models of PD. Emerging research tools include “knockout” rats with disruption of genes in which mutations have been causally linked to PD, including LRRK2, α‐synuclein, Parkin, PINK1, and DJ‐1. Rats have also been increasingly used for transgenic and viral‐mediated overexpression of genes relevant to PD, particularly α‐synuclein. It may not be realistic to obtain a single animal model that completely reproduces every feature of a human disease as complex as PD. Nevertheless, compared with mice with the same mutations, many genetic rat animal models of PD better reproduce key aspects of PD including progressive loss of dopaminergic neurons in the substantia nigra, locomotor behavior deficits, and age‐dependent formation of abnormal α‐synuclein protein aggregates. Here we briefly review new developments in genetic rat models of PD that may have greater potential for identifying underlying mechanisms, for discovering novel therapeutic targets, and for developing greatly needed treatments to slow or halt disease progression. © 2018 International Parkinson and Movement Disorder Society     

Brain region‐dependent differential expression of alpha‐synuclein

α‐Synuclein, the major constituent of Lewy bodies (LBs), is normally expressed in presynapses and is involved in synaptic function. Abnormal intracellular aggregation of α‐synuclein is observed as LBs and Lewy neurites in neurodegenerative disorders, such as Parkinson's disease (PD) or dementia with Lewy bodies. Accumulated evidence suggests that abundant intracellular expression of α‐synuclein is one of the risk factors for pathological aggregation. Recently, we reported differential expression patterns of α‐synuclein between excitatory and inhibitory hippocampal neurons. Here we further investigated the precise expression profile in the adult mouse brain with special reference to vulnerable regions along the progression of idiopathic PD. The results show that α‐synuclein was highly expressed in the neuronal cell bodies of some early PD‐affected brain regions, such as the olfactory bulb, dorsal motor nucleus of the vagus, and substantia nigra pars compacta. Synaptic expression of α‐synuclein was mostly accompanied by expression of vesicular glutamate transporter‐1, an excitatory presynaptic marker. In contrast, expression of α‐synuclein in the GABAergic inhibitory synapses was different among brain regions. α‐Synuclein was clearly expressed in inhibitory synapses in the external plexiform layer of the olfactory bulb, globus pallidus, and substantia nigra pars reticulata, but not in the cerebral cortex, subthalamic nucleus, or thalamus. These results suggest that some neurons in early PD‐affected human brain regions express high levels of perikaryal α‐synuclein, as happens in the mouse brain. Additionally, synaptic profiles expressing α‐synuclein are different in various brain regions. J. Comp. Neurol. 524:1236–1258, 2016. © 2015 Wiley Periodicals, Inc.     

Molecular interaction between parkin and PINK1 in mammalian neuronal cells

Parkinson's disease (PD) is characterized by the deterioration of dopaminergic neurons in the pars compacta of substantia nigra and the formation of intraneuronal protein inclusions. The etiology of PD is not known, but the recent identification of several mutation genes in familial PD has provided a rich understanding of the molecular mechanisms of PD pathology. Mutations in PTEN-induced putative kinase 1 (PINK1) and parkin are linked to early-onset autosomal recessive forms of familial PD. Here we show molecular and functional interactions between parkin and PINK1. Parkin selectively binds to PINK1 and upregulates PINK1 levels. In addition, PINK1 reduces the solubility of parkin, which induces the formation of microtubule-dependent cytoplasmic aggresomes. Our findings reveal that parkin and PINK1 affect each other's stability, solubility and tendency to form aggresomes, and have important implications regarding the formation of Lewy bodies.     

Dopaminergic lesioning impairs adult hippocampal neurogenesis by distinct modification of α‐synuclein

Nonmotor symptoms of cognitive and affective nature are present in premotor and motor stages of Parkinson's disease (PD). Neurogenesis, the generation of new neurons, persists throughout the mammalian life span in the hippocampal dentate gyrus. Adult hippocampal neurogenesis may be severely affected in the course of PD, accounting for some of the neuropsychiatric symptoms such as depression and cognitive impairment. Two important PD‐related pathogenic factors have separately been attributed to contribute to both PD and adult hippocampal neurogenesis: dopamine depletion and accumulation of α‐synuclein (α‐syn). In the acute 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine model, altered neurogenesis has been linked merely to a reduced dopamine level. Here, we seek to determine whether a distinct endogenous α‐syn expression pattern is associated, possibly contributing to the hippocampal neurogenic deficit. We observed a persistent reduction of striatal dopamine and a loss of tyrosine hydroxylase‐expressing neurons in the substantia nigra pars compacta in contrast to a complete recovery of tyrosine hydroxylase‐immunoreactive dopaminergic fibers within the striatum. However, dopamine levels in the hippocampus were significantly decreased. Survival of newly generated neurons was significantly reduced and paralleled by an accumulation of truncated, membrane‐associated, insoluble α‐syn within the hippocampus. Specifically, the presence of truncated α‐syn species was accompanied by increased activity of calpain‐1, a calcium‐dependent protease. Our results further substantiate the broad effects of dopamine loss in PD‐susceptible brain nuclei, gradually involved in the PD course. Our findings also indicate a detrimental synergistic interplay between dopamine depletion and posttranslational modification of α‐syn, contributing to impaired hippocampal plasticity in PD. © 2015 Wiley Periodicals, Inc.     

Nigral burden of α‐synuclein correlates with striatal dopamine deficit

Aggregated α‐synuclein is the hallmark of Parkinson's disease (PD), diffuse Lewy body disease (DLBD), and multiple system atrophy (MSA). Physiologically, α‐synuclein ensures normal functions of dopamine transporter (DAT) and tyrosine hydoxylase. In α‐synucleinopathies, it accumulates in neuronal cytoplasm and neurites through several stages. It is unclear whether the accumulation of pathological α‐synuclein in the substantia nigra in PD correlates with the dopaminergic deficit in the striatal target. We evaluated the impact of the nigral burden of pathological α‐synuclein immunoreactivity in 27 α‐synucleinopathy brains by morphometric immunohistochemistry. DAT immunoreactivity in the striatum inversely correlates with the total α‐synuclein burden in the substantia nigra but not with cytoplasmic inclusion counts only. This result has implications for imaging, clinicopathological correlative studies, and staging of the disease process. © 2008 Movement Disorder Society     

Neuropathology of Parkinson's disease with the R1441G mutation in LRRK2

We report the neuropathological findings in a patient with Parkinson's disease (PD) associated with Basque R1441G‐LRRK2/dardarin mutation. The patient was a man with disease onset at 68 years of age, with unilateral rest tremor; the Parkinsonism was well controlled with medication for 15 years. He died at the age of 86, after 18 years of evolution. The neuropathological examination disclosed mild neuronal loss in the substantia nigra pars compacta without α‐synuclein, tau, LRRK2, or ubiquitin cytoplasmic inclusions. Lewy bodies and Lewy neurites were absent. This is the first neuropathological study of PD associated with brain with the R1441G mutation in LRRK2. © 2009 Movement Disorder Society     

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.     

The cellular pathology of Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder of unknown cause that occurs in adults. The presence of Lewy bodies (LB) in association with nerve cell loss in the substantia nigra and various other regions of the nervous system is a diagnostic hallmark of the disease. In 1997, a mutation was identified in the α‐synuclein gene in families with autosomal dominant PD. Subsequent immunohistochemical studies have revealed that all of the LB in familial and sporadic PD contain the gene product α‐synuclein: abnormal filaments that constitute LB were clearly recognized by antibodies against α‐synuclein. Moreover, it was shown that the glial cells, both astrocytes and oligodendrocytes, are also affected by α‐synuclein pathology. Recently, a novel protein, synphilin‐1, has been identified that interacts with α‐synuclein. Interestingly, synphilin‐1 immunohistochemistry has demonstrated that this protein is present in the central core of classical (brainstem) LB, which are composed mainly of densely packed vesicular structures. The role of both α‐synuclein and synphilin‐1 in normal conditions has yet to be clarified.     

Absence of prostate apoptosis response-4 protein in substantia nigra of Parkinson's disease autopsies

The morphological evidence for apoptosis of dopaminergic neurons in Parkinson's disease (PD) remains a conflicting issue. The present study examined autopsy material containing substantia nigra and putamen of PD (n=7) and control subjects (n=5) for the expression of prostate apoptosis response-4 (Par-4) protein, a protein expressed by apoptotic cells. Par-4 was not detected in the substantia nigra pars compacta. By contrast, duodenal enterocytes, which served as positive controls and are known to be apoptotic, profoundly expressed Par-4. The present study is in agreement with previous studies of the substantia nigra pars compacta in PD, which failed to detect molecules expressed by apoptotic cells. The absence of Par-4 immunoreactivity suggests that death of dopaminergic neurons in PD follows a degenerative pathway that circumvents the induction of Par-4.     

Parkin and PINK1 parkinsonism may represent nigral mitochondrial cytopathies distinct from Lewy body Parkinson's disease

Recent authors have concluded that Parkinson's disease (PD) is too heterogeneous to still be considered a single discrete disorder. They advise broadening the concept of PD to include genetic parkinsonisms, and discard Lewy pathology as the confirmatory biomarker. However, PD seen in the clinic is more homogeneous than often recognized if viewed from a long-term perspective. With appropriate diagnostic criteria, it is consistently associated with Lewy neuropathology, which should remain the gold standard for PD diagnostic confirmation. PD seen in the clinic has an inexorable course with eventual development of not only levodopa-refractory motor symptoms, but often cognitive dysfunction and prominent dysautonomia. This contrasts with homozygous parkin, PINK1 or DJ1 parkinsonism, characterized by young-onset (usually <40 years), and a comparatively benign course of predominantly levodopa-responsive symptoms without dementia or prominent dysautonomia. Parkin neuropathology is non-Lewy, with neurodegeneration predominantly confined to substantia nigra (and locus ceruleus), consistent with the limited clinical phenotype. Given the restricted and persistently levodopa-responsive phenotype, these familial cases might be considered “nigropathies”. Based on emerging laboratory evidence linking parkin and PINK1 (and perhaps DJ1) to mitochondrial dysfunction, these nigropathies may represent nigral mitochondrial cytopathies. The dopaminergic substantia nigra is uniquely vulnerable to mitochondrial challenges, which might at least be partially attributable to large energy demands consequent to thin, unmyelinated axons with enormous terminal fields. Although sporadic PD is also associated with mitochondrial dysfunction, Lewy neurodegeneration represents a more pervasive disorder with perhaps a second, or different primary mechanism.     

The Lewy body in Parkinson's disease: Molecules implicated in the formation and degradation of α‐synuclein aggregates

The histological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates called Lewy bodies (LBs). LB formation has been considered to be a marker for neuronal degeneration, because neuronal loss is found in the predilection sites for LBs. To date, more than 70 molecules have been identified in LBs, in which α‐synuclein is a major constituent of LB fibrils. α‐synuclein immunohistochemistry reveals that diffuse cytoplasmic staining develops into pale bodies via compaction, and that LBs arise from the peripheral portion of pale bodies. This α‐synuclein abnormality is found in 10% of pigmented neurons in the substantia nigra and more than 50% of those in the locus ceruleus in PD. Recent studies have suggested that oligomers and protofibrils of α‐synuclein are cytotoxic, and that LBs may represent a cytoprotective mechanism in PD.     

Brain-derived neurotrophic factor and substantia nigra dopaminergic neurons in Parkinson''s disease

BACKGROUND:Parkinson's disease (PD) is a chronic, progressive neurodegenerative central nervous system disease which occurs in the substantia nigra-corpus striatum system. The main pathological feature of PD is selective dopaminergic neuronal loss with distinctive Lewy bodies in populations of surviving dopaminergic neurons. In the clinical and neuropathological diagnosis of PD, brain-derived neurotrophic factor mRNA expression in the substantia nigra pars compacta is reduced by 70%, and surviving dopaminergic neurons in the PD substantia nigra pars compacta express less brain-derived neurotrophic factor (BDNF) mRNA (20%) than their normal counterparts. In recent years, knowledge surrounding the relationship between neurotrophic factors and PD has increased, and detailed pathogenesis of the role of neurotrophic factors in PD becomes more important.     

硫辛酸对帕金森病小鼠模型自噬蛋白表达水平的影响

目的 探讨硫辛酸(lipoic acid,LA)对MPTP诱导的C57BL/6帕金森病(Parkinson's disease,PD)小鼠模型黑质及纹状体TH、parkin、PINK1、DJ-1自噬相关蛋白表达水平的影响。方法 将60只C57BL/6小鼠随机分为PD模型组、正常组、治疗组、预保护组,采用背部皮下注射MPTP制作PD模型(每组各15只),行为学评价造模,Western Blotting法检测黑质、纹状体TH、parkin、PINK1、DJ-1蛋白的表达水平,免疫组化法观察黑质及纹状体阳性神经元数,免疫荧光检测PINK1的表达水平。结果(1)与正常组比较,PD模型组小鼠黑质、纹状体内TH、Parkin、PINK1、DJ-1的表达水平均明显降低(P<0.01);(2)与PD模型组比较,预保护组黑质、纹状体内TH、PINK1、Parkin、DJ-1表达水平均明显增高(P<0.05);(3)与治疗组比较,预保护组小鼠黑质、纹状体内TH、PINK1、Parkin表达水平略增高,预保护组DJ-1表达水平略降低,但两组比较无统计学差异(P>0.05)。结论 线粒体自噬参与PD小鼠的发病过程; 硫辛酸可能通过上调PD小鼠自噬相关蛋白的表达水平而发挥对多巴胺神经元的保护作用,从而为PD的防治提供新的思路。     

The genetic background of Parkinson's disease: current progress and future prospects

Almost two decades of genetic research in Parkinson's disease (PD) have remarkably increased our knowledge regarding the genetic basis of PD with numerous genes and genetic loci having been found to cause familial PD or affect the risk for PD. Approximately 5–10% of PD patients have monogenic forms of the disease, exhibiting a classical Mendelian type of inheritance, however, the majority PD cases are sporadic, probably caused by a combination of genetic and environmental risk factors. Nowadays, six genes, alpha synuclein, LRRK2, VPS35, Parkin, PINK1 and DJ‐1, have definitely been associated with an autosomal dominant or recessive PD mode of inheritance. The advent of genome‐wide association studies (GWAS) and the implementation of new technologies, like next generation sequencing (NGS) and exome sequencing has undoubtedly greatly aided the identification on novel risk variants for sporadic PD. In this review, we will summarize the current progress and future prospects in the field of PD genetics.     

The usual suspects,dopamine and alpha‐synuclein,conspire to cause neurodegeneration

Parkinson's disease (PD) is primarily a movement disorder driven by the loss of dopamine‐producing neurons in the substantia nigra (SN). Early identification of the oxidative properties of dopamine implicated it as a potential source of oxidative stress in PD, yet few studies have investigated dopamine neurotoxicity in vivo. The discovery of PD‐causing mutations in α‐synuclein and the presence of aggregated α‐synuclein in the hallmark Lewy body pathology of PD revealed another important player. Despite extensive efforts, the precise role of α‐synuclein aggregation in neurodegeneration remains unclear. We recently manipulated both dopamine levels and α‐synuclein expression in aged mice and found that only the combination of these 2 factors caused progressive neurodegeneration of the SN and an associated motor deficit. Dopamine modified α‐synuclein aggregation in the SN, resulting in greater abundance of α‐synuclein oligomers and unique dopamine‐induced oligomeric conformations. Furthermore, disruption of the dopamine‐α‐synuclein interaction rescued dopaminergic neurons from degeneration in transgenic Caenorhabditis elegans models. In this Perspective, we discuss these findings in the context of known α‐synuclein and dopamine biology, review the evidence for α‐synuclein oligomer toxicity and potential mechanisms, and discuss therapeutic implications. © 2019 International Parkinson and Movement Disorder Society     

WIN55,212-2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

Parkinson’s disease (PD) is characterized by the progressive loss of nigrostriatal dopamine neurons leading to motor disturbances and cognitive impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to prevent or slow down the disease progression. In this study, we investigated the molecular mechanisms by which the non‐selective cannabinoid receptor agonist WIN55,212‐2 (WIN) protects mouse nigrostriatal neurons from 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced neurotoxicity and neuroinflammation. Stereological analyses showed that chronic treatment with WIN (4 mg/kg, intraperitoneal), initiated 24 h after MPTP administration, protected against MPTP‐induced loss of tyrosine hydroxylase‐positive neurons in the substantia nigra pars compacta independently of CB₁ cannabinoid receptor activation. The neuroprotective effect of WIN was accompanied by increased dopamine and 3,4‐dihydroxyphenylacetic acid levels in the substantia nigra pars compacta and dorsal striatum of MPTP‐treated mice. At 3 days post‐MPTP, we found significant microglial activation and up‐regulation of CB₂ cannabinoid receptors in the ventral midbrain. Treatment with WIN or the CB₂ receptor agonist JWH015 (4 mg/kg, intraperitoneal) reduced MPTP‐induced microglial activation, whereas genetic ablation of CB₂ receptors exacerbated MPTP systemic toxicity. Furthermore, chronic WIN reversed MPTP‐associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults using the inverted grid test. In conclusion, our data indicate that agonism at CB₂ cannabinoid receptors protects against MPTP‐induced nigrostriatal degeneration by inhibiting microglial activation/infiltration and suggest that CB₂ receptors represent a new therapeutic target to slow the degenerative process occurring in PD.     

Recessive Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease caused by loss of dopaminergic neurons in the substantia nigra pars compacta. Although the etiology of PD remains unclear, it is now clear that genetic factors contribute to the pathogenesis of the disease. Recently, several causative genes have been identified in monogenic forms of PD. Accumulating evidence indicates that their gene products play important roles in mitochondrial function, oxidative stress response, and the ubiquitin-proteasome system, which are also implicated in sporadic PD, suggesting that these gene products share a common pathway to nigral degeneration in both familial and sporadic PD. Here, we review recent advances in knowledge about genes associated with recessive PD, including parkin, PINK1, and DJ-1.     

Treatments of Parkinson disease: circa 2003

Parkinson disease (PD) is a progressive degenerative neurological disorder characterized by resting tremor, bradykinesia, cogwheel rigidity, and postural instability.1 In the later stages, approximately 25% or more of patients develop cognitive compromise. The cardinal pathological features of PD are degeneration of dopaminergic neurons in the substantia nigra pars compacta and their axons, which project principally to the caudate and putamen, and the presence of eosinophilic intracytoplasmic inclusions, Lewy bodies.2-3 Although the loss of neurons is most conspicuous in the substantia nigra pars compacta, neuronal loss and/or Lewy bodies are found in other brain regions (eg, the locus coeruleus, entorhinal region, and amygdala),2 which suggests that treatments that target only the nigrostriatal dopaminergic system, though they may substantially benefit patients, are unlikely to completely resolve the deficits of PD.     

Erythropoietin is neuroprotective in a transgenic mouse model of multiple system atrophy

Multiple system atrophy is a rapidly progressive neurodegenerative disorder with a markedly reduced life expectancy. Failure of symptomatic treatment raises an urgent need for disease‐modifying strategies. We have investigated the neuroprotective potential of erythropoietin in (proteolipid protein)‐α‐synuclein transgenic mice exposed to 3‐nitropropionic acid featuring multiple system atrophy‐like pathology including oligodendroglial α‐synuclein inclusions and selective neuronal degeneration. Mice were treated with erythropoietin starting before (early erythropoietin) and after (late erythropoietin) intoxication with 3‐nitropropionic acid. Nonintoxicated animals receiving erythropoietin and intoxicated animals treated with saline served as control groups. Behavioral tests included pole test, open field activity, and motor behavior scale. Immunohistochemistry for tyrosine hydroxylase and dopamine and cyclic adenosine monophosphate‐regulated phosphoprotein (DARPP‐32) was analyzed stereologically. Animals receiving erythropoietin before and after 3‐nitropropionic acid intoxication scored significantly lower on the motor behavior scale and they performed better in the pole test than controls with no significant difference between early and late erythropoietin administration. Similarly, rearing scores were worse in 3‐nitropropionic acid‐treated animals with no difference between the erythropoietin subgroups. Immunohistochemistry revealed significant attenuation of 3‐nitropropionic acid‐induced loss of tyrosine hydroxylase and DARPP‐32 positive neurons in substantia nigra pars compacta and striatum, respectively, in both erythropoietin‐treated groups without significant group difference in the substantia nigra. However, at striatal level, a significant difference between early and late erythropoietin administration was observed. In the combined (proteolipid protein)‐α‐synuclein 3‐nitropropionic acid multiple system atrophy mouse model, erythropoietin appears to rescue dopaminergic and striatal gabaergic projection neurons. This effect is associated with improved motor function. Further studies are warranted to develop erythropoietin as a potential interventional therapy in multiple system atrophy. © 2011 Movement Disorder Society     

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