24 March 2005. 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.
Yazawa I, Giasson BI, Sasaki R, Zhang B, Joyce S, Uryu K, Trojanowski J, Lee VM. Mouse model of multiple system atrophy α-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron. 2005 Mar 24;45:847-859.