Multiple systems atrophy (MSA) is a progressive neurodegenerative disorder that results from the accumulation of insoluble α-synuclein throughout the CNS. Often misclassified as Parkinson’s disease because of its similar motor disturbances, MSA differs from PD and other synucleinopathies in that the troublesome protein aggregates appear predominantly in oligodendrocytes rather than neurons.

To try to mimic this rather unique disease in a mouse, Virginia Lee and her colleagues at the University of Pennsylvania School of Medicine engineered animals with a human α-synuclein gene that was highly expressed only in oligodendrocytes. Their results, published today in Neuron, show that the transgenic mice display a slowly progressive neurodegenerative condition with many of the hallmarks of human MSA. The mice accumulate insoluble filamentous α-synuclein in oligodendrocytes, leading to a primary loss of the glial cells and a secondary neuronal degeneration. This model of glial-driven neurodegeneration provides a new opportunity for probing the causes and cures of human MSA, and possibly other diseases including AD and ALS, where non-neuronal cells are increasingly implicated in neuropathology (see ARF related news story).

The MSA mice, expressing human α-synuclein driven by the glial-specific CNP promoter, appear normal and have a normal life span. Starting at three months of age, however, they begin to lose motor skills and paw strength. Their decline was associated with brain atrophy, and the brains of two-year-old transgenic mice were grossly smaller that those of normal mice. In addition, the researchers, led by first author Ikuru Yazawa, measured a decrease in both neurons and oligodendrocyte number in the spinal cord. An age-dependent accumulation of filamentous aggregates of synuclein bore a striking resemblance to the glial cytoplasmic inclusions (GCIs) that are diagnostic for human MSA. Fine structural analysis showed degenerating glial cells and autophagocytosis of myelin. Nerve cells likewise showed markers of injury and structural evidence of degeneration. An unexpected finding was that the nerve cells in older mice started to express high levels of mouse α-synuclein in their axons, presumably in response to oligodendrocyte degeneration.

“Our mice not only recapitulated many features of MSA neuropathology, but also proved evidence that secondary neuronal degeneration can occur as a direct consequence of oligodendrocytic GCI-like pathologies,” write the authors. Normal glial cells express very low levels of α-synuclein, and what triggers the synucleinopathy in human MSA is still a mystery. Understanding this rare disease may lead to insights into other, more common neurodegenerative diseases including AD and PD, in which a common thread is the abnormal accumulation of misfolded proteins in the brain, Lee said.—Pat McCaffrey

Pat McCaffrey is a science writer in Newton, Massachusetts.

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  1. Multiple system atrophy (MSA) is a devastating neurodegenerative disorder that presents with a variety of symptoms that can be categorized broadly into two phenotypic groups, either parkinsonism or cerebellar ataxia. These phenotypes reflect the predominant neuronal cell loss that occurs in several brain regions including caudate, putamen, substantia nigra, cerebellum, pons, inferior olives, and spinal cord. The pathogenic hallmark of MSA is the presence of glial cytoplasmic inclusions (GCIs) in oligodendroglia of affected brain regions. GCIs are protein aggregates that contain an abundance of α-synuclein, which implicates this neuronal protein in a central role for MSA pathogenesis despite its normal absence from oligodendroglia.

    Since the first description of GCIs, MSA researchers have wondered whether the disease process begins in neurons or oligodendroglia. This important question is perhaps best addressed by developing MSA animal models that mimic the pathological and behavioral aspects of the disease. Animal models of MSA have proven difficult to generate because they often fail to replicate the entire scope of glial pathology and neuronal cell loss. By developing a transgenic mouse that overexpresses human α-synuclein in oligodendroglia via the oligodendroglia-specific CNP promoter, Yazawa and colleagues (Yazawa et al., 2005) have effectively recapitulated many aspects of MSA. Not only do M2 mice exhibit GCI formation in oligodendroglia, they also display a slow progression of behavioral deficits that are preceded by neuronal deficits (e.g., axonal atrophy) in cerebrum and spinal cord. Loss of neurons and oligodendroglia was revealed only in spinal cord. The sequence of these events suggests that oligodendroglial abnormalities are the primary cause of MSA.

    This work further establishes a critical role for α-synuclein in MSA pathology and neurodegeneration. It supports the prediction that an overabundance of α-synuclein in oligodendroglia is a key event in MSA pathogenesis. However, α-synuclein is not normally expressed in oligodendroglia of mouse brain (Yazawa et al., 2005) or human brain (Solano et al., 2000). Clearly, a future advance in MSA research will be determining the cause for ectopic overabundance of α-synuclein in GCI-containing oligodendroglia.

    Curiously, the M2 mice lack neuronal cell loss in many brain regions commonly affected in MSA, such as substantia nigra. This indicates that α-synuclein overexpression alone is not adequate for truly replicating the complexities of MSA pathology. Future studies will likely examine whether substantia nigra and other brain regions are more vulnerable to toxic insults in M2 mice than in non-transgenic mice. Perhaps neuronal vulnerability to mitochondrial inhibitors such as 3-nitroproprionic acid will be enhanced in M2 mice, as was recently demonstrated in similar mice that overexpress α-synuclein in oligodendroglia via the proteolipid protein (PLP) promoter (Stefanova et al., 2005). Such evidence supports the idea of a “multi-hit” scheme for MSA pathogenesis in which mitochondrial dysfunction may play a role.

    Along with PLP-α-synuclein mice (Kahle et al., 2002), the M2 mice provide the means to examine the potential downstream effects of α-synuclein overabundance in oligodendroglia. Such analysis will likely reveal toxic mechanisms of neuronal cell death in MSA, thereby providing novel targets for MSA therapeutics. Hopefully, other diseases in which glial deficits lead to neuronal cell loss will also benefit from such advances.

    References:

    . Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes. EMBO Rep. 2002 Jun;3(6):583-8. PubMed.

    . Expression of alpha-synuclein, parkin, and ubiquitin carboxy-terminal hydrolase L1 mRNA in human brain: genes associated with familial Parkinson's disease. Ann Neurol. 2000 Feb;47(2):201-10. PubMed.

    . Oxidative stress in transgenic mice with oligodendroglial alpha-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy. Am J Pathol. 2005 Mar;166(3):869-76. PubMed.

    . Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron. 2005 Mar 24;45(6):847-59. PubMed.

References

News Citations

  1. ALS—Is It the Neurons or the Glia?

Further Reading

Primary Papers

  1. . Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron. 2005 Mar 24;45(6):847-59. PubMed.