Abstract
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 manuscript, relevant published evidence is interpreted and integrated into a comprehensive hypothesis on the nature, origin, and inter-cellular 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 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.
Highlights
Parkinson's disease (PD) is one of the most common neurodegenerative disorders, yet the etiology of the majority of its cases remains unknown
We argued for the hematopoietic stem cell niche as a possible site for the appearance of a primordial PD-state cell based on evidence that supports: i) PD patients consistently having circulating hematopoietic cells in the PD-state; ii) Those hematopoietic cells more plausibly having acquired the PD-state at hematopoiesis, rather than after maturation; and iii) The critical role of reactive oxygen species (ROS) in regulating the
Based on recently published findings that we considered relevant to the PD field, as well as on various established lines of PD research, we presented a comprehensive theory on the nature, origin, and intercellular mode of propagation of sporadic Parkinson's disease
Summary
Valente[1,2,3], Altynai Adilbayeva4,Tursonjan Tokay[4], Albert A.
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