Targeting the Chameleon: a Focused Look at α-Synuclein and Its Roles in Neurodegeneration

Abstract

A prehistory of Parkinson’s disease (PD) is given in an article published in 2004 [1]. Here, Garcia Ruiz argues that PD has been known since the pre-Biblical times, with descriptions of parkinsonian symptoms being found in Indian texts, Egyptian papyruses, the Bible, and in the Galen’s writing. Although these symptoms were also mentioned by several authors in the seventeenth and eighteenth centuries [1], the real official history of this disease starts in 1817, when a British physician James Parkinson described the characteristic clinical symptoms of PD and the way of the disease progresses over time, in a paper entitled “An essay of the shaking palsy” [2]. Parkinson observed a small group of six individuals with similar symptoms, such as resting tremor, abnormal posture and gait, paralysis, and diminished muscle strength, which he believed to form a unique affliction, which he referred to as “shaking palsy” or “paralysis agitants.” These observations were further developed and deepened by early neurologists, including Jean-Martin Charcot, who made the distinction between the primary PD symptoms, namely rigidity, weakness, and bradykinesia, and also proposed to rename shaking palsy to Parkinson’s disease in honor of James Parkinson [3]. The primary clinical symptoms of PD at the onset of the disease are muscular rigidity, resting tremors, and bradykinesia (slowing of voluntary movement). As PD progresses, other symptoms become more apparent, such as a fixed and expressionless face, postural instability, akinesia (impaired body movement), depression, and cognitive incompetence. Over time, Parkinson’s observations were refined and other symptoms, such as anosmia (loss of olfaction), were pinpointed. In general, anosmia appears during the early stages of PD, but it goes unnoticed by most health care workers. Only keen and experienced physicians with a good understanding of PD can detect this symptom as a warning signal. As a group, these symptoms have been labeled as “the cardinal PD symptoms” [4–6]. It took almost a hundred years to advance from the stage of finding, describing, and proving the major clinical symptoms of PD to new levels, which provide a more mechanistic understanding of the PD pathology. This transition was made by the pioneering work of Frederic Lewy, who discovered microscopic particles (later named Lewy bodies in his honor [7]) in affected brains, and by the studies of Konstantin Tretiakoff, who, based on a postmortem study of the substantia nigra, provided first solid evidence that this brain region was the main cerebral structure affected by the idiopathic and post-encephalitic parkinsonism [8]. This observation gave strong support to the hypothesis formulated by Edouard Brissaudbased that the substantia nigra could be the major pathological site in Parkinson’s disease [9]. Brissaudbased’s hypothesis was based on the results of the autopsy of a patient with unilateral parkinsonian tremor reported by Paul Blocq and Georges Marinesco, which showed an encapsulated B. A. Silva Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA