Abstract
Parkinson's disease, the most common movement disorder, results in an insidious reduction for patients in quality of life and ability to function. A hallmark of Parkinson's disease is the brain accumulation of neuronal cytoplasmic inclusions comprised of the protein α-synuclein. The presence of α-synuclein brain aggregates is observed in several neurodegenerative diseases, including dementia with Lewy bodies and Lewy body variant of Alzheimer's disease. These disorders, as a group, are termed synucleinopathies. Mounting evidence indicates that α-synuclein amyloid pathology may spread during disease progression by a prion-like (self-templating alteration in protein conformation) mechanism. Clear in vitro and cell culture data demonstrate that amyloidogenic α-synuclein can readily induce the conversion of other α-synuclein molecules into this conformation. Some data from experimental mouse studies and autopsied brain analyses also are consistent with the notion that a self-promoting process of α-synuclein amyloid inclusion formation may lead to a progressive spread of disease in vivo. However, as pointed out in this review, there are alternative explanations and interpretations for these findings. Therefore, from a therapeutic perspective, it is critical to determine the relative importance and contribution of α-synuclein prionlike spread in disease before embarking on elaborate efforts to target this putative pathogenic mechanism.
Highlights
Parkinson’s disease, the most common movement disorder, results in an insidious reduction for patients in quality of life and ability to function
In addition to displaying neuronal loss and neuro-inflammation, most Parkinson’s disease (PD) brains display the presence of intracytoplasmic inclusions known as Lewy bodies (LBs) and Lewy neurites (LNs) in some of the remaining dopaminergic neurons of the substantia nigra pars compacta (SNpc), but many other neuronal populations are affected [9,10,11,12]
LBs and LNs are formed as a result of the aberrant amyloid-type aggregation of the neuronal presynaptic protein α-synuclein [12,13,14]. α-Synuclein neuronal inclusions can present in a spectrum of neurodegenerative disorders, termed synucleinopathies, as exemplified by the more widespread presentation of LBs and LNs in the brains of patients with the disorder dementia with LBs (DLB) [12,13]
Summary
Parkinson’s disease, the most common movement disorder, results in an insidious reduction for patients in quality of life and ability to function. There is evidence that Aβ and neurofibrillary tangle pathologies can spread in a similar prion-type mechanism as α-synuclein and that αsynuclein may cross-seed both of these pathologies [15], but in this review we will focus only on the findings directly involving α-synuclein.
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