Biomedical Research Foundation Academy Of AthensAcademy Of Athens
Research Highlights :Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models


Maria Xilouri and colleagues recently published a study in Acta Neuropathologica.

Multiple system atrophy (MSA) is a rare neurological disorder associated with the degeneration of nerve cells in specific areas of the brain and affects both men and women of all racial groups.  MSA, also known as Shy-Drager Syndrome, causes a combination of symptoms that affect the body’s involuntary (autonomic) functions such as blood pressure, digestion, breathing, and muscle control. The disorder causes the affected nerve cells in the brain and spinal cord to progressively lose function and eventually die. Specifically, MSA is characterized by the accumulation of cytoplasmic inclusions filled with the neuronal protein alpha-synuclein within oligodendrocytes. Oligodendrocytes are a selective type of glial cells that provide support and insulation to neuronal axons, creating the myelin sheath around them. Accumulation of alpha-synuclein together with the oligodendrocyte-specific protein TPPP/p25α ultimately leads to oligodendroglial degeneration and neuronal demise.

In the current study we aimed to identify the mechanisms underlying the abnormal accumulation of alpha-synuclein in oligodendrocytes and to uncover the role of p25α in MSA development and progression. The ultimate goal was to pinpoint novel potential therapeutic targets for MSA and related brain diseases. Utilizing in vitro and in vivo experimental models of MSA we demonstrate for the first time that endogenous oligodendroglial alpha-synuclein, however minute in amount at baseline, is a major component of such insoluble, highly aggregated, pathological assemblies. Interestingly, the overexpression of p25α accelerates the recruitment of endogenous protein and the generation of such aberrant species. In primary oligodendrocytes and in the mouse brain, the microtubule and myelin networks are disrupted, thus recapitulating a pathological hallmark of MSA, in a manner totally dependent upon the seeding of endogenous alpha-synuclein, since these phenomena are not observed in mice lacking alpha-synuclein expression.

Such data suggest that endogenous alpha-synuclein and oligodendroglial phosphoprotein p25α form a dangerous dynamic duo that predisposes oligodendrocytes to accumulate intracellular alpha-synuclein aggregates reminiscent of the oligodendroglial inclusions in MSA brains. Importantly, the identification of endogenous oligodendroglial alpha-synuclein as a major culprit for the development of pathology in vitro and in vivo, suggests that manipulation of the expression of alpha-synuclein in oligodendrocytes, may provide a rationale approach to combat its accumulation and the progression of MSA. An alternative strategy may involve lowering p25α levels, as these also correlate with MSA-type pathology.


Mavroeidi P, Arvanitaki F, Karakitsou AK, Vetsi M, Kloukina I, Zweckstetter M, Giller K, Becker S, Sorrentino ZA, Giasson BI, Jensen PH, Stefanis L, Xilouri M. Endogenous oligodendroglial alpha-synuclein and TPPP/p25α orchestrate alpha-synuclein pathology in experimental multiple system atrophy models. Acta Neuropathol. 2019 Apr 22. doi: 10.1007/s00401-019-02014-y.