Early versus Later Cellular Changes in Patients with Synucleinopathies

Professor Glenda Halliday
Neuroscience Research Australia and the University of New South Wales, Sydney
18 October 2012 - 12:00pm
Rountree Room 356, Level 3, Biological Sciences Building

If anyone would like to meet with Prof Halliday please contact the School Office.

Synucleins are soluble proteins structurally resembling apolipoproteins tat are primarily found in neural tissue. Synuclein mutations cause neurological diseases with cellular inclusions made from insoluble synuclein protein. Three distinct types of inclusions (Lewy bodies and neurites, oligodendroglial cytoplasmic inclusions (GCI), and axonal spheroids) occur in different neurological syndromes - idiopathic Parkinson's disease (PD) and dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and a number of rarer neuroaxonal dystrophies.

The pathology observed in PD is more rapid in patients with an older compared with younger onset of symptoms. Patients with coexisting age-related pathologies also have a more rapid disease. Cytosolic a-synuclein is dramatically increased in the amount it is phosphorylated, and as the disease progresses there is an increase in membrane associated a-synuclein with a high proportion of a-synuclein phosphorylated. Although insoluble fibrillar intracellular inclusions occur only in neurons, astrocytes also accumulate non-fibrillar a-synuclein, and the degree of astrocytic a-synuclein relates to the degree of phagocyte activity in the tissue.

Mutations in ß-synuclein are a rare cause of DLB. Unlike the other major synucleinopathies, DLB patients also deposit extracellular ß-amyloid in addition to a-synuclein. ß-synculein inhibits the aggregation of both a-synuclein and ß-amyloid, and the loss of ß-synuclein function is likely to significantly enhance the aggregation of both proteins.
MSA patients have a much shorter disease course and more widespread neuronal loss in association with a-synuclein deposition in GCI. In affected oligodendroglia there is a rapid increase in soluble a-synuclein. Direct comparison with PD shows significantly less a-synuclein phosphorylation in MSA (~50% less over the same time period), with the increased overall amount of soluble a-synuclein in MSA relocating primarily to membrane-rich oligodendroglia (~20x more membrane-associated a-synuclein in MSA over the same time period) and not becoming highly insoluble.

This data shows different mechanisms for a-synuclein aggregation in the major forms of synucleinopathy. For Lewy pathology sustained cytosolic phosphorylation of neuronal a-synuclein appears to be the critical step in the slow formation of pathological inclusions, whereas the relatively rapid relocation of increased amounts of a-synuclein to oligodendroglial membranes in MSA is consistent with the pathological inclusions associated with this disorder.