Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a Prion-Like Disorder?

Research output: Contribution to journalReview article


Altered protein handling is thought to play a key role in the etiopathogenesis of Parkinson's disease (PD), as the disorder is characterized neuropathologically by the accumulation of intraneuronal protein aggregates (Lewy bodies and Lewy neurites). Attention has particularly focused on the alpha-synuclein protein, as it is the principal component of Lewy pathology. Moreover, point mutations in the alpha-synuclein gene cause rare familial forms of PD. Importantly, duplication/triplication of the wild type alpha-synuclein gene also cause a form of PD, indicating that increased levels of the normal alpha-synuclein protein is sufficient to cause the disease. Further, single nucleotide polymorphisms in the alpha-synuclein gene are associated with an increased risk of developing sporadic PD. Recent evidence now suggests the possibility that alpha-synuclein is a prion-like protein and that PD is a prion-like disease. Within cells, alpha-synuclein normally adopts an alpha-helical conformation. However, under certain circumstances, the protein can undergo a profound conformational transition to a beta-sheet-rich structure that polymerizes to form toxic oligomers and amyloid plaques. Recent autopsy studies of patients with advanced PD who received transplantation of fetal nigral mesencephalic cells more than a decade earlier demonstrated that typical Lewy pathology had developed within grafted neurons. This suggests that alpha-synuclein in an aberrantly folded, beta-sheet-rich form had migrated from affected to unaffected neurons. Laboratory studies confirm that alpha-synuclein can transfer from affected to unaffected nerve cells, where it appears that the misfolded protein can act as a template to promote misfolding of host alpha-synuclein. This leads to the formation of larger aggregates, neuronal dysfunction, and neurodegeneration. Indeed, recent reports demonstrate that a single intracerebral inoculation of misfolded alpha-synuclein can induce Lewy-like pathology in cells that can spread from affected to unaffected regions and can induce neurodegeneration with motor disturbances in both transgenic and normal mice. Further, inoculates derived from the brains of elderly alpha-synuclein-overexpressing transgenic mice have now been shown to accelerate the disease process when injected into the brains of young transgenic animals. Collectively, these findings support the hypothesis that alpha-synuclein is a prion-like protein that can adopt a self-propagating conformation that causes neurodegeneration. We propose that this mechanism plays an important role in the development of PD and provides novel targets for candidate neuroprotective therapies. (C) 2013 Movement Disorder Society


  • C. Warren Olanow
  • Patrik Brundin
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology


  • misfolded alpha-synuclein, beta-sheet formation, Lewy-like pathology, prions, toxic oligomers
Original languageEnglish
Pages (from-to)31-40
JournalMovement Disorders
Issue number1
Publication statusPublished - 2013
Publication categoryResearch

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Neuronal Survival (013212041)