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Novel therapeutic approaches in multiple system atrophy

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Abstract

Multiple system atrophy (MSA) is a sporadic, adult onset, relentlessly progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism, cerebellar dysfunction, pyramidal signs, or combinations thereof. Treatments that can halt or reverse the progression of MSA have not yet been identified. MSA is neuropathologically defined by the presence of α-synuclein-containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic α-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprises cell-to-cell transmission of α-synuclein in a prion-like manner, α-synuclein aggregation, increased oxidative stress, abnormal expression of tubulin proteins, decreased expression of neurotrophic factors, excitotoxicity and microglial activation, and neuroinflammation. In an attempt to block each of these pathogenic mechanisms, several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA. These include sertraline, paroxetine, and lithium, which hamper arrival of α-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflammatory drugs, which inhibit α-synuclein aggregation in oligodendrocytes; riluzole, rasagiline, fluoxetine and mesenchymal stem cells, which exert neuroprotective actions; and minocycline and intravenous immunoglobulins, which reduce neuroinflammation and microglial activation. These and other potential therapeutic strategies for MSA are summarized in this review.

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Acknowledgments

HK receives research support from the National Institutes of Health (NIH) U54NS065736. The Autonomic Disorders Consortium (U54NS065736) is a part of the NIH Rare Diseases Clinical Research Network (RDCRN), supported through collaboration between the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS), and the NINDS. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. JAP receives support from The Dysautonomia Foundation, Inc. We acknowledge The Multiple System Atrophy (MSA) Coalition for supporting the 24th International Symposium on the Autonomic Nervous System where this paper was initially presented.

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  1. Department of Neurology, Dysautonomia Center, New York University School of Medicine, 530 First Av, Suite 9Q, New York, NY, 10016, USA

    Jose-Alberto Palma & Horacio Kaufmann

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Correspondence to Horacio Kaufmann.

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Palma, JA., Kaufmann, H. Novel therapeutic approaches in multiple system atrophy. Clin Auton Res 25, 37–45 (2015). https://doi.org/10.1007/s10286-014-0249-7

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