A Possible Mechanism for the Propagation of Pathological Proteins in Parkinson’s Disease

Abstract

Parkinson’s disease is a common neurodegenerative disorder which recently has come to be regarded as a prion-like foldopathy, the latter term implying that the intercellular trafficking of abnormally folded proteins transmits disease between cells and produces pathology in target cells through the induction of a mis-folded state in normal protein in those cells. In the case of Parkinson’s disease, the prion-like protein primarily involved is alpha-synuclein and inclusions of this protein called Lewy Bodies are commonly found in the substantia nigra of affected patients. Over recent years considerable evidence has been developed to show that a variety of extracellular signaling molecules called intracrines can act in the intracellular space of their cells of synthesis or in target cells after intercellular trafficking. Thus there is some commonality between intracrinephysiology and the pathophysiology of prion-like foldopathies such as Parkinson’s disease. Here these issues and a possible nexus between Parkinson’s disease and intracrine biology are discussed. kuru, mad cow disease, and related disorders result from infection with proteinaceous infectious particles, or prions, which although apparently containing no nucleic acid can infect normal cells and propagate by inducing pathological, infectious conformational changes in their normal protein homologues. Thus the ingestion of infected tissue can introduce infectious prions to an individual and these prions can then spread to the brain where they propagate through neural tissue and produce neurodegeneration. Subsequently, it became apparent that other neurodegenerative disorders while not strictly infectious in terms of easy transfer between infected persons or animals, display characteristics of prion biology in that they appear to spread through neural tissue. Included among these disorders are Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease. In Alzheimer’s disease, the predominant, but often not the sole, prion-like proteins appear to be beta-amyloid and tau, in amyotrophic lateral sclerosis, SOD-1 or TD43, and in the case of Parkinson’s disease, alpha-synuclein. The spread of infectivity in Parkinson’s disease from patient brain to transplanted cells is consistent with this idea of prion-like spread in PD [6-12].