What would Dr. James Parkinson think today? The role of genetics in Parkinson's disease

A renaissance man in the age of Enlightenment, the doctor, geologist, and social reformer James Parkinson was a true visionary in many respects. Parkinson provided us not only with the description of Parkinson’s disease (PD) but also with carefully crafted hypotheses on its etiology, a thorough understanding of which— as he was convinced—would lay the necessary groundwork for a potential cure: “By their [the anatomists’] benevolent labours its real nature may be ascertained, and appropriate modes of relief, or even of cure, pointed out. ” Today, Parkinson would have broadened the term anatomist to include the geneticist and molecular biologist whom he would view as an “anatomist of ultrastructure. ” Accordingly, he would have agreed with Polymeropoulos’ concluding sentence in his 1997 revolutionary Science paper on the discovery of a-synuclein mutations as the first monogenic cause of PD that “even if the mutation. is directly related to only a small fraction of the total number of PD patients, it provides a clue that should lead to the understanding of the underlying pathways resulting in the symptoms of PD. ” Given the absence of genetics as an etiologic concept at that time—Gregor Mendel published his work on the “invisible factors,” that is, genes, half a century later—the overall rare occurrence of large PD families with multiple affected members, and James Parkinson’s focus on elderly patients with likely idiopathic PD, it is not surprising that family history was not an issue in his 1817 “An Essay on the Shaking Palsy. ” Today, James Parkinson would rightfully remind us of the long-held dogma of PD as a textbook example of a nonhereditary condition, which was only truly revised with the advent of PD genetics at the end of the 20th century, thus occupying a mere 10% of the time bar of the 200-year history of PD. However, he would have read with great interest the approximately 20 reports of multiple affected siblings and family members suffering from “paralysis agitans” published in the late 19th and early 20th centuries drawing first attention to a potential role of heritable factors in PD. Indeed, Leroux, one of Charcot’s scholars, concluded as early as 1880 that “heredity is the true, perhaps even the only true cause of paralysis agitance. ” In his original report, James Parkinson described 6 patients with PD whom he had examined or casually met on the street and in whom he was unable to “ascribe its origin to any more obvious cause. ” Therefore, he resorted to the only possible means at that time and derived his considerations on the etiology of PD from analogy, that is, he based his hypotheses about the etiology of PD on the presumed causes of disorders with comparable clinical signs and symptoms. Although James Parkinson would be well aware of the causal heterogeneity of similar phenotypic entities today, he already stressed the speculative nature and limitations of such etiologic deliberations in his original article: “Conjecture founded on analogy, and an attentive consideration of the peculiar symptoms of the disease, have been the only guides that could be obtained for this research, the result of which is, as it ought to be, offered with hesitation. ” In addition, when trying to establish association or even causality today, Parkinson would specifically point to the importance of sample size, now known to be one, if not the major, determinant of valid findings regarding the etiologic architecture of PD as well as of investigations in the later genetics and genomewide association study era. Still, in his analogies, James Parkinson specifically mentioned trauma as a potential cause of PD in the case of the Count de Lordat who developed signs of PD after having survived a severe injury as well as possible inflammation in the context of rheumatoid arthritis in 2 other patients. Today, James Parkinson would be intrigued to learn that not only head trauma and inflammation have reemerged as possibly relevant for PD some 200 years later but that they may even be connected to genetic factors, as evidenced by risk alleles in the HLA (major histocompatibility complex) region -----------------------------------------------------------*Correspondence to: Christine Klein, Institute of Neurogenetics, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany; christine.klein@neuro.uni-luebeck.de