α-Synuclein strains cause distinct synucleinopathies after local and systemic administration.

Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases, but differences in protein components and affected brain regions. The molecular hallmark of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are megadalton α-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial α-synuclein (α-SYN) filamentous deposits are prominent in multiple system atrophy and neuronal α-SYN inclusions are found in Parkinson's disease and dementia with Lewy bodies. The discovery of α-SYN assemblies with different structural characteristics or 'strains' has led to the hypothesis that strains could account for the different clinico-pathological traits within synucleinopathies. In this study we show that α-SYN strain conformation and seeding propensity lead to distinct histopathological and behavioural phenotypes. We assess the properties of structurally well-defined α-SYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that α-SYN strains amplify in vivo. Fibrils seem to be the major toxic strain, resulting in progressive motor impairment and cell death, whereas ribbons cause a distinct histopathological phenotype displaying Parkinson's disease and multiple system atrophy traits. Additionally, we show that α-SYN assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct α-SYN strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes.

The Early Onset of Levodopa-induced Dyskinesia in a Patient with Multiple System Atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by Parkinsonism, cerebellar ataxia, and autonomic dysfunction. While less frequent than Parkinson's disease, MSA patients with a beneficial levodopa response may occasionally present with levodopa-induced dyskinesia (LID). We herein report a 50-year-old woman diagnosed with MSA-parkinsonism who developed LID in the unilateral lower extremity 10 months after the start of levodopa treatment. In this case, the distribution of LID, the timing of its onset, and the presence of LID despite relatively poor levodopa responsiveness were distinctive.

Drug- and Toxin-Induced Opsoclonus - a Systematized Review, including a Case Report on Amantadine-Induced Opsoclonus in Multiple System Atrophy.

Background: Opsoclonus is a rare disorder characterized by conjugate multidirectional, horizontal, vertical, and torsional saccadic oscillations, without intersaccadic interval, resulting from dysfunction within complex neuronal pathways in the brainstem and cerebellum. While most cases of opsoclonus are associated with autoimmune or paraneoplastic disorders, infectious agents, trauma, or remain idiopathic, opsoclonus can also be caused by medications affecting neurotransmission. This review was prompted by a case of opsoclonus occurring in a patient with Multiple System Atrophy, where amantadine, an NMDA-receptor antagonist, appeared to induce opsoclonus. Methods: Case report of a single patient and systematized review of toxic/drug-induced opsoclonus, selecting articles based on predefined criteria and assessing the quality of included studies. Results: The review included 30 articles encompassing 158 cases of toxic/drug-induced opsoclonus. 74% of cases were attributed to bark scorpion poisoning, followed by 9% of cases associated with chlordecone intoxication. The remaining cases were due to various toxics/drugs, highlighting the involvement of various neurotransmitters, including acetylcholine, glutamate, GABA, dopamine, glycine, and sodium channels, in the development of opsoclonus. Conclusion: Toxic/drug-induced opsoclonus is very rare. The diversity of toxics/drugs impacting different neurotransmitter systems makes it challenging to define a unifying mechanism, given the intricate neuronal pathways underlying eye movement physiology and opsoclonus pathophysiology.

Behavioral and histological analysis of a partial double-lesion model of parkinson-variant multiple system atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disease with progressive autonomic failure, cerebellar ataxia (MSA-C), and parkinsonism (MSA-P) resulting from neuronal loss in multiple brain areas associated with oligodendroglial cytoplasmic α-synuclein inclusion bodies. No effective treatments exists, and MSA-P patients often fail to respond to L-DOPA because of the loss of striatal dopaminergic receptors. Rendering MSA-P patients sensitive to L-DOPA administration following striatal tissue transplantation has been proposed as a possible novel therapeutic strategy to improve the clinical condition. Here we describes simple, skilled, and sensorimotor behavior deficits in a unilateral partial double-lesion (DL) rat model of MSA-P. The sequential striatal double-lesion model mimicks early MSA-P pathology by combining partial 6-hydroxydopamine (6-OHDA) followed by striatal quinolinic acid (QA) lesion. Animals were tested on spontaneous, learned, or drug-induced behavioral tasks on multiple occasions pre- and postsurgery. The data show robust, lateralized deficits, and the partial 6-OHDA and the double-lesioned animals were most impaired. Importantly, this study identified a behavioral deficit profile unique to the double-lesion animals and distinctive from the single 6-OHDA- or the QA-lesioned animals. Histology confirmed an approximately 40% dopamine loss in the striatum in the 6-OHDA and double-lesion animals as well as a similar loss of striatal projection neurons in the QA and double-lesion animals. In summary, we have established the behavioral deficit profile of a partial double-lesion rat model mimicking the early stage of MSA-P.

Evaluation of a multiple system atrophy model in rats using multitracer microPET.

BACKGROUND: A double toxin-double lesion strategy is appropriate for mimicking of striatonigral degeneration. Because knowledge of human pathology is limited, animal models must be well characterized prior to testing of therapeutic approaches to treat multiple system atrophy. In double-toxin animal models, however, reduced contralateral rotation after apomorphine injection is restored within a few weeks via an unknown mechanism; the animals thus revert to PD status. We assessed this phenomenon using multitracer microPET and tissue staining. METHODS: Five adult male Wistar rats received injections of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle (MFB), followed 3 weeks later by injections of quinolinic acid (QA) into the ipsilateral striatum. Apomorphine-induced rotation tests were performed 1 week after each injection, and 6 and 10 weeks after QA injection. Rotarod tests were performed weekly after 6-OHDA injection. MSA-p status was characterized by microPET 5 and 10 weeks after QA injection using the tracers 2-deoxy-2-[(18)F]-fluoro-D-glucose ([(18)F]-FDG) and [(18)F]-N-(3-fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl)nortropane ([(18)F]-FP-CIT). Histological changes were evaluated by tyrosine hydroxylase (TH) and cresyl violet staining. RESULTS: The numbers of apomorphine-induced rotations increased contralaterally after 6-OHDA lesions were created, but decreased significantly after QA administration (p = 0.007). Five weeks after QA injection, however, contralateral rotation again increased and persisted for 1 month. Rotarod rotation differed significantly between the intact and PD states (p < 0.05), but not between the PD and MSA-p states. MicroPET revealed glucose hypometabolism and dopamine transporter (DAT) impairment on the lesioned side of the striatum 1 and 2 months after QA lesion surgery. Loss of nigral cells was confirmed by TH immunostaining, and striatal atrophy was observed upon cresyl violet staining. CONCLUSION: Pathological changes consistent with MSA-p can be generated by the double toxin-double lesion method and persist during follow-up. Behavioral tests, such as drug-induced rotation and rotarod tests, are not appropriate for long-term follow-up in the MSA-p model, suggesting the need for development of more appropriate behavioral tests.

Neuroprotective Effect of a DJ-1 Based Peptide in a Toxin Induced Mouse Model of Multiple System Atrophy.

Multiple System Atrophy (MSA) is a sporadic neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and dysautonomia, in various combinations. In MSA with parkinsonism (MSA-P), the degeneration is mainly restricted to the substantia nigra pars compacta and putamen. Studies have identified alterations in DJ-1 (PARK7), a key component of the anti-oxidative stress response, in Parkinson's disease (PD) and MSA patients. Previously we have shown that a short DJ-1-based peptide named ND-13, protected cultured cells against neurotoxic insults and improved behavioral outcome in animal models of Parkinson's disease (PD). In this study, we used the 3-Nitropropionic acid (3-NP)-induced mouse model of MSA and treated the animals with ND-13 in order to evaluate its therapeutic effects. Our results show that ND-13 protects cultured cells against oxidative stress generated by the mitochondrial inhibitor, 3-NP. Moreover, we show that ND-13 attenuates nigrostriatal degeneration and improves performance in motor-related behavioral tasks in 3-NP-treated mice. Our findings suggest a rationale for using ND-13 as a promising therapeutic approach for treatment of MSA.

Multiple system atrophy: the putative causative role of environmental toxins.

BACKGROUND: Whereas a number of studies have investigated the putative role of environmental toxins in the pathogenesis of idiopathic Parkinson disease, the possibility of such a role in multiple system atrophy has received little attention. DESIGN AND SETTING: Review of records of patients examined in the Parkinson's Disease Center and Movement Disorder Clinic, Baylor College of Medicine, Houston, Tex, from July 1, 1977, to February 4, 1998. PATIENTS: We reviewed 100 consecutive medical records of patients who satisfied the diagnostic criteria for multiple system atrophy formulated by the Consensus Committee of the American Autonomic Society and the American Academy of Neurology. INTERVENTION: The type and amount of toxin exposure were verified by history and examination of records whenever possible. Severity of parkinsonism was assessed by clinical rating scales. MAIN OUTCOME MEASURE: Development of multiple system atrophy after environmental toxin exposure. RESULTS: Eleven patients had a notable history of heavy exposure to environmental toxins. One patient with multiple system atrophy confirmed by postmortem evaluation was exposed to high concentrations of malathion, diazinon, and formaldehyde, while the other patients with multiple system atrophy had well-documented high exposures to agents including n-hexane, benzene, methyl isobutyl ketone, and pesticides. The case studied pathologically demonstrated extensive advanced glial changes, including glial cytoplasmic inclusions in deep cerebellar white matter, brainstem, cortex (superior frontal, insula) and putamen, with notable cell loss and depigmentation of the substantia nigra and locus ceruleus. CONCLUSION: While many studies report a possible role of environmental toxins in Parkinson disease, such a role is even more likely in multiple system atrophy, as this is a sporadic disease.

Complex motor disturbances in a sequential double lesion rat model of striatonigral degeneration (multiple system atrophy).

This study characterizes paw reaching, stepping and balance abnormalities in a double lesion rat model of striatonigral degeneration, the core pathology underlying levodopa unresponsive parkinsonism associated with multiple system atrophy. Extensive unilateral nigral or striatal lesions induced by 6-hydroxydopamine or quinolinic acid, respectively, produced a similarly marked contralateral paw reaching deficit without further deterioration following a secondary (complementary) lesion of ipsilateral striatum or substantia nigra. Contralateral stepping rates were reduced by unilateral 6-hydroxydopamine lesions without further deterioration following the secondary striatal lesion. In contrast, initial unilateral striatal quinolinic acid injections induced bilateral stepping deficits that significantly worsened contralaterally following the secondary nigral lesion. Contralateral sidefalling rates were significantly increased following primary nigral and striatal lesions. Secondary nigral but not secondary striatal lesions worsened contralateral sidefalling rates. Histological studies revealed subtotal (>90%) depletion of dopaminergic neurons in substantia nigra pars compacta and variable degrees of striatal degeneration depending on the lesion sequence. Animals pre-lesioned with 6-hydroxydopamine showed significantly larger residual striatal surface areas following the secondary striatal quinolinic acid lesion compared to animals with primary striatal quinolinic acid lesions (P<0.001). These findings are in line with previous experimental studies demonstrating that striatal dopamine depletion confers neuroprotection against subsequent excitotoxic injury. Whether loss of dopaminergic neurons protects against the striatal disease process occurring in multiple system atrophy (Parkinson-type) remains to be elucidated. In summary, this is the first experimental study to investigate spontaneous motor behaviour in a unilateral double lesion rat model. Our observations are consistent with a complex interaction of nigral and striatal lesions producing distinct behavioural and histological changes depending on the lesion sequence. Tests of forelimb akinesia and complex motor behaviour appear to provide a reliable tool that will be helpful for monitoring the effects of interventional strategies such as embryonic neuronal transplantation in the rat model of striatonigral degeneration.

Multiple system atrophy following chronic carbon disulfide exposure.

Carbon disulfide toxicity is well characterized. The principal target organ is the nervous system, although cardiovascular, reproductive, ophthalmologic, and other effects are also recognized. The neurotoxicity manifests in three ways: encephalopathy, peripheral and cranial nerve dysfunction, and movement abnormalities. This report describes a case of olivopontocerebellar atrophy, a form of multiple system atrophy, developing in an adult after over 30 years of occupational exposure to carbon disulfide. The patient presented with the insidious onset of balance problems, impotence, and irritability, without tremor, cogwheel rigidity, bradykinesia, or changes in facial expression. Over the next few years severe ataxia developed, and the clinical diagnosis was confirmed with computed tomography and magnetic resonance imaging scans. The patient experienced multiple medical complications and died approximately 9 years after diagnosis. This case is consistent with a large body of clinical and experimental literature, much of it 50 years old, showing that carbon disulfide can cause movement disorders. It also serves as a reminder that movement disorders, ranging from parkinsonism to dystonia, are associated with a variety of toxic exposures such as manganese, carbon monoxide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and medications.

Multisystem atrophy made worse by lithium treatment in a hospice patient: a case report.

Multisystem atrophy is a neurologic condition defined as an adult-onset, progressive, neurodegenerative disease of unknown etiology. It carries a multisystem clinical course, including autonomic, urogenital, cerebellar, and parkinsonian features. Lithium toxicity, classically manifesting as increased thirst, polyuria, gastric distress, weight gain, tremor, fatigue, and mild cognitive impairment, can present in a similar manner.(1) We would like to present a patient diagnosed with progressive neurologic features typical of multisystem atrophy that also had bipolar disorder and had been taking lithium for many years. Despite normal lithium levels, it appeared as though a subclinical lithium toxicity was manifesting in the patient, and once lithium was discontinued, the patient was discharged from hospice with significant improvement in his presenting symptoms.

Animal models of multiple system atrophy.

Multiple system atrophy (MSA) is a sporadic adult-onset neurodegenerative disorder clinically characterized by a variable combination of dysautonomia, levodopa-unresponsive parkinsonian and cerebellar symptoms. Neurodegeneration in MSA occurs in the substantia nigra, putamen, inferior olive, pontine and brainstem nuclei, as well as intermediolateral cell column of the spinal cord. MSA is recognized as a synucleinopathy due to the accumulation of insoluble alpha-synuclein in oligodendroglial cytoplasmic inclusions. Several animal models have been developed in order to reproduce various clinical and pathological features of MSA. Using "double toxin-double lesion" or "single toxin-double lesion", neurotoxin-based models were designed in rats, mice and non-human primates to reproduce the neuropathology of MSA in the nigrostriatal system while gene-based models were developed in mice to reproduce the accumulation of insoluble alpha-synuclein in oligodendrocytes. Both approaches have then been merged to create optimized, dual-hit models. This review describes the different animal models of MSA, their respective advantages and limitations and their usefulness to decipher the pathophysiology of MSA then to define efficient symptomatic and disease-modifying therapies. This article is part of a Special Issue entitled: Neuroscience Disease Models.

Neuroprotective effect of human mesenchymal stem cells in an animal model of double toxin-induced multiple system atrophy parkinsonism.

Multiple system atrophy (MSA) is an adult-onset sporadic neurodegenerative disorder of unknown etiology featuring parkinsonism, ataxia, and autonomic failure in any combination. Because disease progression in MSA is rapid and no drug treatment consistently benefits MSA patients in the long term, neuroprotective or regenerative strategies may be invaluable in the management of MSA patients. In this study, we investigated whether human mesenchymal stem cells (hMSCs) had a protective effect on MSA using an animal model of double-toxin-induced MSA parkinsonism (MSA-P). MSA-P was established with coinjections of MPTP and 3-NP; hMSCs were injected into the tail vein 1 day after the last toxin injection. Three groups of mice were compared (i.e., control, MPTP + 3-NP, and MPTP + 3-NP with hMSC treatment) through histopathological, behavioral, and Western blot analyses. In the substantia nigra (SN) and the striatum, 2.0% and 3.8% of total injected hMSCs were observed, respectively. Compared with double-toxin-treated mice, hMSC treatment in double-toxin-treated mice significantly increased survival of TH- and NeuN-immunoreactive cells in the SN and the striatum, with coincident improvement in motor behavior. Additionally, hMSC treatment significantly decreased double-toxin-induced microglial and astroglial activation in the SN and striatum. Western blot analysis showed that hMSC administration in double-toxin-treated mice increased the expression of p-Akt and Bcl-2 and decreased Bax and cytochrome c expression. This study demonstrates that hMSC treatment protected against loss of neurons in the SN and the striatum induced by double toxin exposure, which may be mediated by modulation of inflammatory and cell survival and death signaling-pathway as the hMSCs migrated from the peripheral circulation into the SN and striatum.

Alpha-synuclein deficient mice are resistant to toxin-induced multiple system atrophy.

Multiple systems atrophy (MSA) is a neurodegenerative disorder characterized by oligodendrocytic accumulations of alpha-synuclein (alphasyn). Oxidative stress is a key mechanism proposed to underlie MSA pathology. To address the role of alphasyn modifications, over and above general oxidative modifications, this study examined the effects of 3-nitropropionic acid (3NP) administration, a technique used to model MSA, in knock-out mice lacking alphasyn (alphasynKO). Although susceptible to 3NP-induced oxidative stress, alphasynKO mice display reduced neuronal loss and dendritic pathology. The alphasynKO mice are resistant to 3NP-induced motor deficits and display attenuated loss of tyrosine hydroxylase and dopamine transporter striatal immunoreactivity. The results suggest that deficits in MSA are not due to general oxidative protein modification but in addition may be related to specific alphasyn modifications.

Rasagiline is neuroprotective in a transgenic model of multiple system atrophy.

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

Loss of dopaminergic responsiveness in a double lesion rat model of the Parkinson variant of multiple system atrophy.

The Parkinson variant of multiple system atrophy (MSA-P) is a distinct atypical parkinsonian disorder with a loss of dopaminergic neurons comparable to that found in Parkinson's disease (PD). The additional loss of striatopallidal projections is thought to account for levodopa unresponsiveness in MSA-P. Whereas histological features of MSA-P have been successfully reproduced in the double lesion rat model, loss of levodopa responsiveness has so far not been demonstrated. In the current study, 6-hydroxydopamine (6-OHDA) induced unilateral lesions of the substantia nigra produced a marked contralateral forelimb stepping deficit, which improved significantly after challenge with levodopa (P < 0.001). This response was abolished by the subsequent striatal quinolinic acid (QA) lesion. In the cylinder test, the marked asymmetry observed after 6-OHDA lesioning was reversed by levodopa to baseline levels. After QA, cylinder test performance under levodopa failed to reach baseline (P = 0.001) or 6-OHDA + levodopa (P = 0.002) levels. Nigral cell loss (90% +/- 5%) correlated with both stepping test (r = 0.608; P = 0.008) and cylinder test results (r = 0.656; P = 0.005). Lesion extent of the dorsal striatum correlated significantly with the loss of levodopa response (r = 0.593; P = 0.01) in the stepping test. These findings contribute further to the behavioral characterization of the double lesion rat model of MSA, improving its value in the evaluation of future neurorestorative strategies.