Is Parkinson’s disease a prion disease?

In the 1990s, a small cohort of patients with PD received striatal transplants of foetal dopaminergic neurons in an attempt to compensate for lost capacity in the substantia nigra.^4,5 The brain of one of these patients was examined after her death 14 years later.^4,5 During the examination, it was observed that some of the grafted neurons in the patient’s brain tissue contained Lewy body-like inclusions that stained positively for α-synuclein, indicating its presence in the tissue.⁵ Although the patient had responded well to dopaminergic therapy for several years after her transplant, her symptoms had worsened again over time, which suggests that the striatal transplants had deteriorated due to α-synuclein-related pathology.⁵ This finding was subsequently confirmed in several similar clinical cases and replicated in animal models, including an experiment in which α-synuclein fibrils were injected into the olfactory bulb of mouse brains.^6,7 These fibrils ‘recruited’ normal α-synuclein to become insoluble aggregates, which then spread into other areas of the brain, causing loss of olfactory function.⁷

When viewed as a prion-like disease, there are some new avenues to studying PD aetiology that open up.⁸ There are some in vitro α-synuclein fibrillization assays, cell models of α-synuclein spreading, and animal models that can be used to study prion pathology.⁸ Moreover, the prion-like features of PD could be used to stage PD, with the potential of powerful new biomarkers and early diagnosis.⁸

References:
1.Brundin P, Ma J, Kordower JH. How strong is the evidence that Parkinson’s disease is a prion disorder? Curr Opin Neurol 2016; 29 (4): 459–466.

2.Jan A, Gonçalves NP, Vaegter CB, et al. The prion-like spreading of alpha-synuclein in Parkinson’s disease: update on models and hypotheses. Int J Mol Sci 2021; 22 (15): 8338.

3.Woerman AL, Tamgüney G. Body-first Parkinson’s disease and variant Creutzfeldt–Jakob disease – similar or different? Neurobiol Dis 2022; 164: 105625.

4.Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 2001; 344 (10): 710–719.

5.Kordower JH, Chu Y, Hauser RA, et al. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med 2008; 14 (5): 504–506.

6.Stopschinski BE, Diamond MI. The prion model for progression and diversity of neurodegenerative diseases. Lancet Neurol 2017; 16 (4): 323–332.

7.Rey NL, Steiner JA, Maroof N, et al. Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease. J Exp Med 2016; 213 (9): 1759–1778.

8.Scialò C, Legname G. How would defining Parkinson’s as a prion disease impact the search of a cure? Expert Rev Neurother 2020; 20 (5): 417–420.