The Universal Non-Neuronal Nature of Parkinson ' s Disease : A Theory

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, yet the etiology of the majority of its cases remains unknown. In this article, relevant published evidence is interpreted and integrated into a comprehensive hypothesis on the nature, origin and intercellular mode of propagation of sporadic PD. We propose to characterize sporadic PD as a pathological deviation in the global gene expression program of a cell: the PD expression-state, or PD-state for short. A universal cell-generic state, the PD-state deviation would be particularly damaging in a neuronal context, ultimately leading to neuron death and the ensuing observed clinical signs. We review why ageing associated accumulated damage caused by oxidative stress in mitochondria could be the trigger for a primordial cell to shift to the PD-state. We propose that hematopoietic cells could be the first to acquire the PD-state, at hematopoiesis, from the disruption in reactive oxygen species (ROS) homeostasis that arises with age in the hematopoietic stem-cell niche. We argue that cellular ageing is nevertheless unlikely to explain the shift to the PD-state of all the subsequently affected cells in a patient, thus indicating the existence of a distinct mechanism of cellular propagation of the PD-state. We highlight recently published findings on the inter-cellular exchange of mitochondrial DNA and the ability of mitochondrial DNA to modulate the cellular global gene expression state and propose this could form the basis for the inter-cellular transmission of the PD-state. INTRODUCTION Parkinson’s disease (PD) is a common neurodegenerative disorder associated with old age. The number of worldwide affected individuals is estimated at 7 to 10 million. With population ageing, particularly in developing countries, this number is expected to increase steeply in the upcoming decades. Unfortunately, there is currently no cure for PD, with available medications only providing symptomatic relief. PD is a movement disorder clinically characterized by tremor, bradykinesia, rigidity, and postural instability. The motor dysfunctions are a direct consequence of the death of dopamine-producing neurons in the substantia nigra pars compacta region of the midbrain. Histologically, the most noticeable feature of PD are abnormal aggregates of proteins, called Lewy bodies and Lewy neurites, that appear in the cell body and neurites of PD patient neurons. Their major constituent is the protein alpha-synuclein. Familial genetic linkage studies have unequivocally associated six genes with Mendelian inheritable forms of PD. Still, these individual gene mutations account for fewer than 10% of PD cases. They generally lead to juvenile or early onset PD (before 50 years of age). Naturally, genetics still impacts the risk of an individual acquiring non-monogenic sporadic PD later in life. Over a dozen single nucleotide polymorphisms (SNPs) have been statistically linked with sporadic PD through genome-wide association studies (GWASs). However, the differential risks associated with carrying these SNPs, although statistically significant, are mostly very small in absolute terms. Similarly, although some environmental factors, such as exposure to metals or pesticides, have PeerJ Preprints | https://doi.org/10.7287/peerj.preprints. 1314v4 | CC-BY 4.0 Open Access | rec: 14 Apr 2016, publ: 14 Apr 2016 been statistically linked with PD, the associations do not appear to be sufficiently widespread to explain beyond a minority of PD cases. Thus, the etiology of the over 90% of cases classified as sporadic PD remains undetermined. We briefly highlight some of the major theories being pursued regarding the nature of sporadic PD. Different aspects of these hypotheses will be presented in more detail as relevant, throughout the article. An overarching hypothesis on the etiology of sporadic PD is that it is triggered by an external agent. Pesticides and metals would be two candidate environmental agents, given their statistical association with PD. Another proposed factor suggested in the literature is a neurothropic pathogen, such as a virus or a prion-like protein. Entry into the organism could be via the peripheral olfactory system or via the gastrointestinal tract, two sites associated with early prodromal clinical symptoms of PD. These two sites have also been combined into a dual-hit hypothesis, centered on an external agent simultaneously entering the organism via the two routes. Whether with an initially external origin or endogenously generated, the theory that a misfolded, prion-like self-propagating form of alpha-synuclein is responsible for the disease is another major hypothesis currently under investigation. More endogenous, aging-related perspectives of sporadic PD focus on the role of oxidative stress and mitochondrial damage, for which there is significant evidence in PD patients. Finally, although the view of sporadic PD as an autoimmune disease is not typical, the aggravating contribution of the neuro-inflammatory response to the disease is commonly acknowledged. Starting from the analysis of sporadic PD blood gene-expression data, we have previously argued that sporadic PD could have a hematopoietic origin. In the present article, we review and expand on this original hypothesis, placing it in the context of recent developments in both PD and the broader biological research. The article first addresses why sporadic PD may be a systemic, rather than solely neuronal, condition. Then, it discusses why inter-cellular propagation of the pathology may be involved, rather than the pathology being purely associated with cell ageing phenomena. In particular, we present the possibility that the disease transmission may be enabled by the intercellular exchange of the mitochondrial DNA. Finally, the article revisits our previously published hypothesis that the pathology may initially begin at hematopoiesis. THE UNIVERSAL NATURE OF THE PD-STATE In this section we argue for the systemic nature of sporadic PD. Our case is centered on the interpretation of recently published evidence obtained by applying induced pluripotent stem cell (iPSC) technology to PD research. Using iPSC techniques, conveniently collected cells from PD patients, such as skin fibroblasts, can be reverted to a pluripotent state and subsequently differentiated into dopaminergic neurons. We believe that early PD iPSC experimental results support a fundamental re-evaluation of the nature of the sporadic non-monogenic form of the disease. We summarize the main observations from two of the published PD iPSC studies. In both studies, skin fibroblasts from sporadic PD patients (presuppose sporadic henceforth) were reprogrammed back into pluripotent stem cells, which were then differentiated into dopaminergic neurons. Sánchez-Danés et al. reported that, in comparison with neurons derived from fibroblasts from disease-free controls, neurons originating in fibroblasts from PD patients consistently showed PD phenotype associated alterations. These included reduced numbers of neurites, more limited neurite arborizations, and increases in caspase-3 activity, a marker for cell apoptosis. Woodard et al. utilized neurons derived from fibroblasts of two monozygotic twins discordant for PD. Multiple alterations that can be linked with a PD phenotype were present exclusively in the fibroblasts derived from the PD twin. These included lower dopamine levels, an PeerJ Preprints | https://doi.org/10.7287/peerj.preprints. 1314v4 | CC-BY 4.0 Open Access | rec: 14 Apr 2016, publ: 14 Apr 2016 elevated presence of alpha-synuclein in neurites, a delay in the emergence of spontaneous action potentials, and an absence of synchronous neuronal activity. An epidemiological study by Tanner et al. reported a mere 15.5% concordance of monozygotic twins in developing PD. An analogous study in Sweden published by Wirdefeldt et al. corroborated this result, placing the concordance rate at 11%. Thus, excluding the monogenic cases, heredity does not ensure the emergence of PD. Therefore, the consistent, regular emergence of a PD phenotype in neurons derived from fibroblasts from PD patients cannot be attributed to a PD favorable germline genetic background in the patients. The conclusion is that the disease must have been present in the skin fibroblasts from the patients. PD is thus a systemic condition, not confined to neuronal cells. We propose to characterize PD as a pathological deviation in the expression program of a cell: the PD expression-state, or PD-state for short. Reports of a characteristic PD gene-expression signature across multiple tissues support this view. The recent observation of a unique, concordant pattern of methylation in post-mortem frontal cortex samples and peripheral blood leukocytes from PD patients reinforces this standpoint, further suggesting that the PD-state may be stabilized by DNA epigenetic modifications. THE ROLE OF AGEING IN PD In spite of possessing a multitude of self-repair mechanisms, all cells undergo the ageing process. They gradually accumulate dysfunctional molecules, as well as random mutations and other assorted alterations in their genetic code, ultimately resulting in the ageing phenotype. As a source of free radicals, mitochondria and the mitochondrial DNA are particularly vulnerable to oxidative stress damage. This observation has led to the theory that the mitochondrial dysfunction caused by oxidative stress plays a central role in ageing. With PD arising at old age and with mitochondrial function specifically known to be compromised in a variety of cell types in PD patients, the mitochondrial theory of aging broadly views PD as yet another manifestation of this phenomenon. It is conceivable that accumulated random damage, possibly in mitochondrial DNA and due to oxidative stress, eventually triggers the gene expression program of a cell to shift to the PD-state. This shift to the PD-state