Parkinson disease (PD) is a brain disorder characterized by problems with movement and by a loss of neuronal cells (in substantia nigra of the midbrain that produce the neurotransmitter, dopamine). Cause(s) of PD are not clear, although some evidence suggests that disrupted immune function and inflammation (possibly in the gut) might play a role. Clearly, there’s a strong environmental component plus genetic susceptibility. Two proteins, PINK1 [encoded by the PINK1 (PTEN-induced kinase-1) gene] and parkin (encoded by the PRKN gene), regulate the function of mitochondria (the energy-generating organelles in the cell), and these mitochondria become dysfunctional in certain forms of PD.
Authors [see attached article amd editorial) show that, in mice lacking PINK1, an intestinal infection can trigger an immune response that results in production of immune cells that target mitochondrial molecules; this response also causes transient muscle motor impairments — resembling those in clinical PD, plus a temporary loss of neuronal dopamine-release sites. Mutations in human genes encoding PINK1 and parkin have been linked to rare, heritable types of parkinsonian syndromes, the group of tremor disorders to which PD belongs; however, these proteins were long considered mostly irrelevant for the ~90% of cases of PD that occur later in life (known as idiopathic PD), and which are thought to arise from complex interactions between genes and environment.
PINK1 and parkin act together in stressed cells to preserve mitochondrial function; in their absence, damaged mitochondria do
not undergo proper degradation and instead accumulate in the cell. Findings during the past decade suggest that PINK1 and parkin
also have a role in immune function that could implicate these two proteins (gene products) in the development of idiopathic PD. For example, PINK1 limits production of inflammatory molecules called cytokines (various substances – such as interferon, interleukin, and growth factors – which are secreted by certain cells of the immune system and have an effect on other cells in the body), and parkin protects mice against neurodegeneration that is caused by chronic inflammation outside the central nervous system.
Authors [see attached article] found that an intestinal infection with Gram-negative bacteria [chloramphenicol-resistant Citrobacter rodentium, given by oral gavage] in Pink1(−/−) mice elicits mitochondrial antigen presentation and autoimmune mechanisms that lead to establishment of cytotoxic mitochondria-specific CD8+ T cells in peripheral nerves and in the brain. These mice show a sharp decrease in density of dopaminergic axons (the long threadlike parts of nerve cells along which impulses are conducted from the cell body to other cells) in the substantia nigra; the mice are affected by motor impairment that can be reversed by LevoDopa treatment (the same drug used clinically for PD). These results support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in PD. This study also highlights the relevance of the Gut–Brain-Microbiome Axis in this disorder. 😊
Nature 25 July 2019; 571: 565-570 and Editorial pp 481-481
[ first pdf file at left] is a recent article that is very relevant to what these GEITP pages have just been discussing. The simple injection of misfolded a-synuclein fibrils into nerve cells in the gastrointestinal (GI) tract produces a parkinsonian (PD)-like disease in mice several months later. Vagotomy (cutting the vagus nerve) prevents this transmission from gut to brain; thus, vagotomy (and also in these mice, a-synuclein deficiency) prevent the neuropathology and neurobehavioral deficits induced by the transmitted pathological a-synuclein.
The next obvious question is, what environmental factors (e.g. dietary, inhaled, or even through the skin) are capable of triggering this misfolding of a-synuclein? Because late-onset PD is associated with many decades of life, epigenetic effects as well as environmental factors must be in play — along with each patient’s individual genetic architecture.
[Thanks to Wm T Penberthy for pointing out this fascinating article.] 😊
For these GEITP pages, with gene-environment interactions as the overriding theme, Parkinson disease (PD) and parkinsonian syndromes represent “The Perfect Storm.” There are Mendelian genes [e.g. PRKN (parkin RBR E3 ubiquitin protein ligase) and PINK1 (PTEN-induced kinase-1)] that can cause early-onset PD; however, the predominant late-onset sporadic PD and parkinsonian syndromes — clearly complex diseases — represent the contribution of “genetic susceptibility” combined with a substantial amount of environmental exposure — whether it be “what you eat,” “what you inhale,” “what is absorbed through the skin,” or “what might enter the body by any other portal of entry.” The etiology of late-onset sporadic PD and parkinsonian syndromes remains to be discovered.
Braak’s hypothesis states that “sporadic PD might be caused by a pathogen that enters the body via the nasal cavity, and subsequently is swallowed to reach the gut, resulting in formation of Lewy bodies (abnormal aggregates of protein that develop inside nerve cells — associated with and/or contributing to PD, dementia, and other neuromuscular disorders) in the nose and digestive tract — prior to reaching the central nervous system (CNS).” In other words, the disorder begins in the periphery and then moves to the CNS. The physician Heiko Braak in 2003 proposed this pathway of PD progression, which resulted in his being awarded the 2014 Robert A. Pritzker Prize for Leadership in Parkinson Research, conferred annually by The Michael J. Fox Foundation (MJFF).