Too good to be true

Abstract

T wo hundred and one years after the original description of Parkinson' s disease (PD) 1 , its cause and pathogenesis remain to be determined. Over this period of time, many hypotheses have been suggested: an exclusively environmental condition caused by an, as of yet, unidentified toxin; a mitochondrial disorder; a lysosomal condition; a purely genetic disease; the result of an interplay of genetic and environmental disorder; and so on 2 . In the current issue of Arquivos, there is a timely and critical review by Gershanik of the involvement of alpha-synuclein (ASN) and the hypothesis that the disease starts in the gut 3 . According to the hypothesis, mutated ASN originated from the enteric nervous system reaches the dorsal motor nucleus of the vagus. The involvement of this nucleus characterizes Braak PD stage I. From the dorsal motor nucleus of the vagus there is cranial spreading of ASN resulting in stages II through VI. Interestingly, in chapter IV of his essay, Parkinson suggested that the condition he was describing was related to "a diseased state of the medulla spinalis, in that part which is contained in the canal, formed by the superior cervical vertebrae, and extending, as the disease proceeds, to the medulla oblongata. " 1 . Although the hypothesis is elegant and attractive, as Gershanik rightly points out, there are several issues that cast doubt on its validity. In the following paragraphs, I will also discuss other potential caveats of this hypothesis.Firstly, a critical prerequisite of this hypothesis is to accept that ASN has a prion-like behavior. According to this hypothesis, mutated ASN is capable of inducing wild ASN to undergo mutation. As it happens in prion diseases, this mechanism would lead to the spreading of pathology in the brain. Although there is evidence in support of this, particularly in experimental models, many experts argue that the hypothesis overstretches the comparison 4 . Another critical feature of the hypothesis is the existence of ASN in the colonic mucosa. Unfortunately, the picture of this issue is far from clear: many studies have failed to differentiate the colonic mucosa of PD patients from controls regarding the presence of ASN 5 .If we accept that indeed there is uptake by the vagus nerve of mutated ASN originated from the gut, there still remain several inconsistencies in the hypothesis. The first one is related to epidemiological studies. Two surveys of large numbers of individuals from Sweden and Denmark have shown that truncal vagotomy decreases the likelihood of the future development of PD 6,7 . However, the effect size is very modest. For instance, in the Swedish study, the hazard ratio of the incidence of PD in patients who underwent truncal vagotomy, in comparison with control individuals, was 0.78. There are several potential explanations for this result. The first is the possibility that the pathogenic process starts very early in life before the time of the vagotomy. This would allow the brainstem to receive ASN before the procedure, reducing the ben...