Multiple system atrophy

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Wetter T., Collado-Seidel V., Pollmacher T., Yassouridis A., Trenkwalder C. (2000). Sleep and periodic leg movement patterns in drug-free patients with Parkinson s disease and multiple system atrophy. Sleep 23(3), 361-7. 

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TABLE 45-1 a-Synuclein diseases Idiopathic Parkinson s disease Dementia with Lewy bodies Pure autonomic failure REM sleep behavior disorder Lewy body dysphagia Incidental Lewy body disease Inherited Lewy body diseases Multiple system atrophy... 

Glial cytoplasmic inclusions are strongly immunoreac-tive for a-synuclein and filaments isolated from the brains of patients with multiple system atrophy are labeled by a-synuclein antibodies [10]. As in dementia with Lewy bodies, assembled a-synuclein is nitrated and phosphory-lated at S129, and the number of a-synuclein-positive structures exceeds that stained by anti-ubiquitin antibodies, confirming that the accumulation of a-synuclein precedes ubiquitination. Filament morphologies and their staining characteristics were found to be similar to those of filaments extracted from the brains of patients with Parkinson s disease and dementia with Lewy bodies. 

This work revealed an unexpected molecular link between multiple system atrophy and Lewy body diseases. The main difference is that in multiple system atrophy most of the a-synuclein pathology is found in glial cells, whereas in Lewy body diseases most of the pathology is present in nerve cells. 

They have many of the morphological and ultrastructural characteristics of disease filaments [11, 12] (Fig. 45-5). Assembly is a nucleation-dependent process that occurs through its amino-terminal repeats. The carboxy-terminal region, in contrast, is inhibitory. Assembly is accompanied by the transition from random coil to a [3-pleated sheet. By electron diffraction, a-synuclein filaments show a conformation characteristic of amyloid fibers. Under the conditions of these experiments, P- and y-synucleins failed to assemble, consistent with their absence from the filamentous lesions of the human diseases. When incubated with a-synuclein, P- and y-synucleins inhibit the fibrillation of a-synuclein, suggesting that they may indirectly influence the pathogenesis of Lewy body diseases and multiple system atrophy. 

FIGURE 45-5 Filaments extracted from the brains of patients with dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) or assembled from bacterially expressed human a-synuclein (SYN) were decorated by an anti-a-synuclein antibody. The gold particles conjugated to the second antibody appear as black dots. Scale bar lOOnm. 

The new work has established that a neurodegenerative pathway leading from soluble to insoluble, filamentous a-synuclein is central to Lewy body diseases and multiple system atrophy. The development of experimental models of a-synucleinopathies has opened the way to the identification of the detailed mechanisms by which the formation of inclusions causes disease. These model systems have also made it possible to identify disease modifiers that may well lead to the development of the first mechanism-based therapies for these diseases. At a conceptual level, it will be important to understand whether a-synuclein has a role to play in disorders, such as autosomal-recessive juvenile forms of parkinsonism caused by mutations in the Parkin, DJ-1 and PINK-1 genes, or whether there are entirely separate mechanisms by which the dopaminergic nerve cells of the substantia nigra degenerate in Parkinson s disease and in inherited disorders with parkinsonism. 

Varrone, A., Marek, K. L., Jennings, D. et al. 123I 5-CIT SPECT imaging demonstrates reduced density of striatal dopamine transporters in Parkinson s disease and multiple system atrophy. Mov. Disord. 16 1023-1032, 2001. 

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IDIOPATHIC PARKINSONISM MULTIPLE SYSTEM ATROPHY NEUROFIBRILLARY TANGLE TYPE e.g. INDUCED BY NEUROLEPTICS... 

Keywords Parkinson s disease Huntington disease Alzheimer s disease Amyotrophic lateral sclerosis Multiple system atrophy Tauopathies Nucleotide... 

Nonhuman Primate Models. . Multiple System Atrophy (MSA). . ... 

Beal MF (2001) Experimental models of Parkinson s disease. Nat Rev Neurosci 2 325-334 Benatroch EE (2002) New findings on the neuropathology of multiple system atrophy. Auton Neurosci 96 59-62... 

Chrysostome V, Tison F, Yekhlef F, Sourgen C, Baldi 1, Dartigues JF (2004) Epidemiology of multiple system atrophy a prevalence and pilot risk factor study in Aquitaine, France. Neuroepidemiology 23 201-208... 

Lantos PL (1998) The definition of multiple system atrophy a review of recent developments. J Neuropathol Exp Neurol 57 1099-1 111... 

Pang Z, Geddes JW (1997) Mechanisms of cell death induced by the mitochondrial toxin 3-nitropropionic acid acute excitotoxic necrosis and delayed apoptosis. J Neurosci 17 3064-3073 Papp MI, Kahn JE, Lantos PL (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 94 79-100... 

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Spillantini MG, Goedert M (2000) The alpha-synucleinopathies Parkinson s disease, dementia with Lewy bodies, and multiple system atrophy. Ann N Y Acad Sci 920 16-27... 

Wenning GK, Colosimo C, Geser F, Poewe W (2004) Multiple system atrophy. Lancet Neurol 3 93-103... 

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