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What Do We Now Know About Alpha-Synuclein's Role In Parkinson's Disease Pathology?

Trojanowski, J.Q.
MDS: Stockholm, Sweden
Download Presentation: Trojanowski MDS-PD-Lecture-FINAL-6-9-2014.pdf
The landmark discoveries that mutations in the alpha-synuclein (a-syn) gene are pathogenic for Parkinson's disease without (PD) and with dementia (PDD) and that pathological a-syn is the disease protein that forms Lewy bodies (LBs) and Lewy neurites (LNs) in PD/PDD place a-syn at center stage for understanding mechanisms of LB diseases (LBD).

Another more recent PD research advance that may be as transformative as the discovery that a-syn is the disease protein in PD and related synucleinopathies is the the cell-to-cell spread of pathological a-syn.

Briefly, emerging data from several groups raise the provocative, but highly plausible possibility that the progression of PD and related LBD is linked to the cell-to-cell spread of pathological a-syn. These novel insights create avenues of basic and translational research into mechanisms underlying the onset and progression of PD/PDD. Further, emerging data from the PD Progression Marker Initiative (PPMI) re-enforce genetic, neuropathology and experimental studies implicating a-syn in mechanisms of PD neurodegenration by suggesting that the earliest onset of clinical PD is associated with abnormal levels of cerebrospinal fluid (CSF) a-syn.

Thus, alterations in CSF a-syn may signal the onset and progression of PD which could result from the cell-to-cell spread of different pathological a-syn conformers or strains from one CNS region to another accompanied by progressive neurodegeneration. Indeed, different clinicopathological manifestations of LBD could reflect the diverse pathobiological effects of different a-syn strains and CSF biomarkers that detect different pathological species of a-syn could become powerful tools for monitoring the progression and heterogeneous manifestations of PD and related LBD.

Alpha-synuclein Mediated Neurodegeneration In PD/PDD This illustrates hypothetical processes whereby normal a-syn converts into pathological a-syn that fibrillizes and deposits into LBs/LNs in PD/PDD which may be captured by measuring CSF a-syn. Recent data suggest that the progression of PD may be linked to the cell-to-cell spread of pathological species of a-syn.