8/6/2019 Artigo 16- Is Parkinson's Disease a Prion Disorder

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Is Parkinson’s disease a prion disorder?C. Warren Olanowa,1 and Stanley B. Prusinerb

aDepartments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY 10029; and bInstitute

for Neurodegenerative Diseases and Department of Neurology, University of California, San Francisco, CA 94143

I

n this issue of PNAS, Desplats etal. (1) demonstrate that nerve cells

that overexpress tagged -synucleincan transmit the protein to neural

stem cells in both in vitro and in vivomodels. This important study could ex-plain the remarkable finding that humanembryonic dopamine nerve cells im-planted into the striatum of patients

 with Parkinson’s disease (PD) developPD pathology with loss of dopaminemarkers and classic Lewy bodies (2, 3).It also provides insight into how-synuclein pathology might sequen-tially spread throughout the nervoussystem in PD.

PD is an age-related, neurodegenera-tive disease that affects approximatelyone million persons in the UnitedStates. Pathologically, the disease ischaracterized by a loss of dopamineneurons in the substantia nigra parscompacta coupled with proteinaceousinclusions in nerve cells and terminals,known as Lewy bodies and Lewy neu-rites, respectively. PD pathology is alsoknown to affect nondopamine neuronsin the upper and lower brainstem, olfac-tory system, cerebral hemisphere, spinalcord, and autonomic nervous system.The cause of cell death in PD is notknown, but proteolytic stress with theaccumulation of misfolded proteins hasbeen implicated (4).

That the aberrant accumulation of proteins might feature in the pathogene-sis of PD is a reasonable posit, giventhat Lewy bodies, the hallmark of thedisease, are composed of a variety of aggregated proteins. Among these,-synuclein has attracted particular at-tention. -Synuclein is a 140-aa synapticprotein that is unstructured in aqueousbuffers, but adopts an -helical-richconformation when bound to mem-branes (5), and can acquire a -sheet-

rich structure that readily polymerizesinto fibrils when present in high concen-tration or in a mutant form (6).

Mutations in -synuclein have beenreported in association with familial PD(7). More interestingly, cases of familialPD have also been described with dupli-cation and triplication of the wild-typeprotein (8, 9). These findings suggestthat increased production of mutant or

 wild-type -synuclein can by itself leadto the development of PD. Indeed, genedelivery of -synuclein to the substantianigra induces degeneration of dopamineneurons with inclusions that stain for

-synuclein and mirrors the pathology of PD (10). Most cases of PD, however, donot appear to be inherited, but ratheroccur sporadically. In these cases as

 well, -synuclein has been implicatedbecause it is a major component of Lewy bodies and neurites (11). In-creased levels of -synuclein in thesecases might derive from impaired clear-ance of the protein by the lysosome andproteasome, as alterations in these sys-tems have been observed in patients

 with sporadic PD (12, 13). Further, inhi-bition of protein clearance produces do-pamine neuronal degeneration with the

formation of inclusions that stain for-synuclein (14).

Increased levels of -synuclein, re-gardless of cause, can promote self-aggregation and interfere withproteasomal and lysosomal functions,leading to further accumulation of theprotein (15, 16). Thus, increased pro-duction or impaired clearance of -synuclein could initiate a vicious cycle

 with continued accumulation and mis-folding of the protein and the subse-quent formation of potentially toxicoligomers and amyloid fibrils.

The role of -synuclein misfolding inthe pathogenesis of cell death in PD andits potential to spread from one nervecell to another has been highlighted bythe recent discovery that embryonic do-pamine neurons that had been trans-planted into PD patients 11–14 yearsearlier developed PD pathology withclassic Lewy bodies that stained for-synuclein and thioflavin-S (a markerfor -sheet-rich protein polymers) (2, 3).The likelihood that these embryonicneurons had been adversely affected bythe accumulation and misfolding of -synuclein is supported by evidence of 

reduced staining for the dopaminetransporter and tyrosine hydroxylase (insome nerve cells). Because -synuclein-positive inclusions have not previouslybeen seen in such young nerve cells, andbecause the transplants were derivedfrom multiple, genetically unrelated do-nors, it seems likely that the inclusions

Author contributions: C.W.O. and S.B.P. wrote the paper.

The authors declare no conflict of interest.

See companion article on page 13010.

1To whom correspondence should be addressed. E-mail:

warren.olanow@mssm.edu.

Fig. 1. Schematic illustration demonstrating similarities in the relationships between the PrPC protein

and prion diseases, and the -synuclein protein and Parkinson’s disease. ( A) The cellular prion protein

(PrPC) comprises 210 aa. The function of PrPC is unknown. PrPC has a largely -helical conformation and

resides on the surface of cell membranes. When PrP C misfolds, it acquires a high -sheet content and

assembles into rods that coalesce to form amyloid plaques. PrPSc is the sole component of the infectious

prion and can lead to disease in animals and humans (19). ( B) -Synuclein is a protein of 140 aa. The

function of -synuclein is unknown. -Synuclein acquires a largely -helical conformation when it binds

to cell membranes. When -synuclein misfolds, it acquires a high -sheet content and polymerizes into

fibrils that are associated with the formation of Lewy bodies. Overexpression of -synuclein alone can

induce a PD syndrome in animals and humans.

www.pnas.orgcgidoi10.1073pnas.0906759106 PNAS August 4, 2009 vol. 106 no. 31 12571–12572

8/6/2019 Artigo 16- Is Parkinson's Disease a Prion Disorder

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arose as a consequence of factors inher-ent to the PD brain. One possible expla-nation is that misfolded -synuclein wastransmitted from pathologically affectedneurons to healthy grafted embryonicdopamine neurons, and there recruitednascently produced -synuclein tomisfold.

Now come the exciting results of 

Desplats et al. (1) demonstrating that-synuclein can be directly transferredfrom nerve cells that overexpress theprotein to neighboring healthy embry-onic stem cells both in tissue cultureand in transgenic animals. This, in turn,

 was associated with pathological changesin acceptor cells as evidenced by thedevelopment of inclusion bodies andneuronal degeneration with markers of apoptosis. This same mechanism mightaccount for the accumulation of mis-folded -synuclein and the developmentof PD pathology in the implanted dopa-mine neurons. It could also account for

the pathologic findings of Braak et al.(17) in the PD brain, which suggest that-synuclein spreads in a sequential andpredictable manner, beginning in thedorsal motor nucleus in the lower brain-stem and extending to involve upperbrainstem nuclei (including the substan-tia nigra) and cerebral hemispheres. In-deed, it is possible that aggregated-synuclein, frequently detected in auto-nomic plexi of the gastrointestinal tractof neurologically intact individuals who

are suspected of having preclinical PD(18), might be the initial site of -synuclein misfolding.

Based on the available evidence, thereis much to suggest that -synuclein be-haves like a prion, and that PD might bea prion disorder (Fig. 1). Both-synuclein and the cellular form of the

prion protein (PrPC) adopt an -helical-rich conformation under physiologicalconditions, and both are capable of re-folding into a -sheet-rich conformationthat readily aggregates into oligomersand amyloid fibrils. Both of these mis-folded proteins (especially the oli-

gomers) are thought to be toxic and ca-pable of inducing neurodegeneration.Furthermore, protein aggregates formedfrom each of these misfolded proteinscan promote the misfolding of addi-tional wild-type protein, and in this way,act as prion conformers (5, 19, 20). Onecan envision that the continued accumu-lation of misfolded proteins challengesthe capacity of the lysosomal and pro-teasomal systems to clear these un-

 wanted proteins, thus promoting their

further accumulation and the develop-ment of a self-propagating cycle thateventually leads to cell death. Now,there is also evidence that, as in theprion diseases, -synuclein can be di-rectly transmitted from pathologicallyaffected to healthy, unaffected cells,thereby potentially extending the diseaseprocess throughout the nervous system.

It is thus possible that PD is a priondisorder resulting from increased pro-duction and/or impaired clearance of proteins such as -synuclein, leading tomisfolding and the formation of toxicoligomers, aggregates, and cell death.Further, it is possible that -synuclein isa prion protein that can self-aggregateand be transmitted to unaffected cells,thus extending the disease process.While genetic causes represent an obvi-ous source of increased levels of aber-rantly folded -synuclein in familial PDcases, a combination of aging, oxidative

stress, inflammation, environmental tox-ins, hereditary factors, and impairedclearance may all feature in varying waysin causing altered metabolism of -synuclein, resulting in the pathogenesisof sporadic PD. This concept suggests thatdrugs directed toward reducing the forma-tion and/or facilitating the clearance of misfolded -synuclein, so as to arrest orreverse the self-propagation process,might represent a novel therapeutic inter-

 ventions for the treatment of PD.

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CW (2008) Parkinson’s disease pathology in long-term

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19671.

There is much to suggest

that -synuclein behaves

like a prion.

12572 www.pnas.orgcgidoi10.1073pnas.0906759106 Olanow and Prusiner