It’s been nearly a decade since groups in the United States¹ and Sweden² reported alpha synuclein pathology in transplanted cells grafted into the brains of people with Parkinson’s disease. The Lewy body-like inclusions were accompanied by other markers of neuronal dysfunction that apparently developed over 10+ years. The pathology is remarkable because the transplanted cells were young and genetically unrelated to the individuals with Parkinson’s disease, suggesting an ongoing degenerative process in the parkinsonian brain and the presence of a pathological microenvironment.³

The finding of Lewy-like inclusions in transplanted cells led to the hypothesis that Parkinson’s disease could be a type of prion disease, involving  the cell to cell transfer of misfolded alpha synuclein.² Similarities between prion diseases and Parkinson’s disease had been documented in the literature since the early 1990s, but no pathology was observed in the prion protein involved in Creutzfeldt-Jakob’s disease.⁴ The observation of similarities persisted, though, and led to the concept of permissive templating–a process thought to be common to Parkinson’s, Creutzfeldt-Jakob’s, Alzheimer’s, Huntington’s, and other diseases of protein aggregation.⁵

Today, the question of whether alpha synuclein behaves like a prion, transferring its toxic configuration from neuron to neuron, is one of the hottest in Parkinson’s disease. The prion hypothesis has several important things going for it. First, it’s consistent with the apparent progression of Parkinson’s disease from the brainstem and olfactory areas to midbrain regions, and eventually the cortex.⁶ Second, it provides an explanation for the pathology observed in heterologous, transplanted dopaminergic cells.

Yet, not everyone is convinced that the prion concept adequately explains Parkinson’s disease. For one thing, only some neurons are susceptible to death. The prion hypothesis seems to predict that the disease should spread between synaptically coupled neurons, but the pattern of pathology in Parkinson’s disease doesn’t follow the connectome.⁷

Alternate explanations also exist for the alpha synuclein accumulation. For example, alpha synuclein is normally present in the perikarya of fetal cells, appearing at terminals during development and in the presence of adequate transport systems (see comments by Subhojit Roy). Transport systems may not be functioning normally in the implanted cells, which extend axons within the putamen of the host brain but from the substantia nigra to caudate and putamen during normal development. However, the initial functionality of transplanted cells followed only later by pathology is inconsistent with this explanation,¹ but instead favors the prion hypothesis.

Another possibility is that the extracellular matrix of the brain develops abnormalities and can no longer support normal nerve cell function. Few investigators have examined the role of the extracellular matrix in Parkinson’s disease, but several single nucleotide polymorphism and gene expression studies have found alterations in these pathways.^8-10 (See an earlier blog on this topic for additional discussion.) This hypothesis predicts differences in the extracellular matrix of affected and unaffected brain regions—a concept that is amenable to experimentation. Reduced matrix functionality could make neurons vulnerable to alpha synuclein pathology and possibly even prion-like transfer.

The finding of Lewy-like inclusions in transplanted cells was an unexpected discovery that profoundly influenced subsequent research and thinking about neurodegenerative diseases. The prion hypothesis explains this pathology and raises additional questions about selectivity and transmissibility. Time—and maybe other unexpected findings—will tell whether we are headed in the right direction or whether we need to make another detour. It’s also critical to note that these findings were made possible by generous patients who participated in research without any guarantee of improvement and, in the case of transplanted cells, often developed disturbing dyskinesias. Without the ability to view their brains postmortem, researchers would not have made these advances.

***************************

By the way, the story of ventral mesencephalic cell transplantation as a treatment for Parkinson’s disease is an interesting one as told by its pioneers, Anders Bjorklund and Olle Lindvall.  It’s quite amazing that heterologous cells could grow and function in the host brain for more than 20 years without being rejected and with only a 6-month course of immunosuppression.

References

1. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW: Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med. 2008;14(5):504-506. https://www.ncbi.nlm.nih.gov/pubmed/18391962
2.  Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Bjorklund A, Widner H et al: Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med. 2008;14(5):501-503. https://www.ncbi.nlm.nih.gov/pubmed/18391963
3.  Kurowska Z, Englund E, Widner H, Lindvall O, Li JY, Brundin P: Signs of degeneration in 12-22-year old grafts of mesencephalic dopamine neurons in patients with Parkinson’s disease. J Parkinsons Dis. 2011;1(1):83-92. https://www.ncbi.nlm.nih.gov/pubmed/23939259
4.  Jendroska K, Hoffmann O, Schelosky L, Lees AJ, Poewe W, Daniel SE: Absence of disease related prion protein in neurodegenerative disorders presenting with Parkinson’s syndrome. J Neurol Neurosurg Psychiatry. 1994;57(10):1249-1251. PMC485496. https://www.ncbi.nlm.nih.gov/pubmed/7931389
5.  Hardy J: Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: ‘permissive templating’ as a general mechanism underlying neurodegeneration. Biochem Soc Trans. 2005;33(Pt 4):578-581. https://www.ncbi.nlm.nih.gov/pubmed/16042548
6.  Braak H, Del Tredici K, Bratzke H, Hamm-Clement J, Sandmann-Keil D, Rub U: Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson’s disease (preclinical and clinical stages). J Neurol. 2002;249 Suppl 3(III/1-5. https://www.ncbi.nlm.nih.gov/pubmed/12528692
7.  Surmeier DJ, Obeso JA, Halliday GM: Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci. 2017;18(2):101-113. https://www.ncbi.nlm.nih.gov/pubmed/28104909
8.  Edwards YJ, Beecham GW, Scott WK, Khuri S, Bademci G, Tekin D, Martin ER, Jiang Z, Mash DC, ffrench-Mullen J, Pericak-Vance MA et al: Identifying consensus disease pathways in Parkinson’s disease using an integrative systems biology approach. PLoS One. 2011;6(2):e16917. PMC3043094. https://www.ncbi.nlm.nih.gov/pubmed/21364952
9.  Hu Y, Deng L, Zhang J, Fang X, Mei P, Cao X, Lin J, Wei Y, Zhang X, Xu R: A Pooling Genome-Wide Association Study Combining a Pathway Analysis for Typical Sporadic Parkinson’s Disease in the Han Population of Chinese Mainland. Mol Neurobiol. 2016;53(7):4302-4318. https://www.ncbi.nlm.nih.gov/pubmed/26227905
10.  Sandor C, Honti F, Haerty W, Szewczyk-Krolikowski K, Tomlinson P, Evetts S, Millin S, Keane T, McCarthy SA, Durbin R, Talbot K et al: Whole-exome sequencing of 228 patients with sporadic Parkinson’s disease. Sci Rep. 2017;7(41188. PMC5259721. https://www.ncbi.nlm.nih.gov/pubmed/28117402