Redefining the hypotheses driving Parkinson’s diseases research

Abstract

Parkinson’s disease (PD) research has largely focused on the disease as a single entity centred on the development of neuronal pathology within the central nervous system. However, there is growing recognition that PD is not a single entity but instead reflects multiple diseases, in which different combinations of environmental, genetic and potential comorbid factors interact to direct individual disease trajectories. Moreover, an increasing body of recent research implicates peripheral tissues and non-neuronal cell types in the development of PD. These observations are consistent with the hypothesis that the initial causative changes for PD development need not occur in the central nervous system. Here, we discuss how the use of neuronal pathology as a shared, qualitative phenotype minimises insights into the possibility of multiple origins and aetiologies of PD. Furthermore, we discuss how considering PD as a single entity potentially impairs our understanding of the causative molecular mechanisms, approaches for patient stratification, identification of biomarkers, and the development of therapeutic approaches to PD. The clear consequence of there being distinct diseases that collectively form PD, is that there is no single biomarker or treatment for PD development or progression. We propose that diagnosis should shift away from the clinical definitions, towards biologically defined diseases that collectively form PD, to enable informative patient stratification. N-of-one type, clinical designs offer an unbiased, and agnostic approach to re-defining PD in terms of a group of many individual diseases.

Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

“…Moreover, an increasing body of recent research implicates peripheral tissues and non-neuronal cell types in the development of PD. These observations are consistent with the hypothesis that the initial causative changes for PD development need not occur in the central nervous system [ 429 ]. The clear consequence of there being distinct diseases that collectively form PD is that there is no single biomarker or treatment for PD development or progression.…”

“…To enable informative patient stratification, an important conclusion for physicians and neurologists is that diagnosis should shift away from the clinical definitions toward biologically defined diseases that collectively form PD. A personalized or N-of-one type clinical designs offer an unbiased and agnostic approach to re-defining PD in terms of a group of many individual diseases [ 429 ].…”

Alpha Synuclein: Neurodegeneration and Inflammation

“…The authors concluded that the involvement of peripherical organs did not distinguish all PD/LBD subjects from controls, and consequently, synucleinopathies must first be in the brain [ 151 ]. A more rational interpretation is that in the majority of DLB cases and less than 20% of PD cases, α-Syn pathology propagation is exclusively in the CNS, but although the peripheral involvement is partial, we could not rule out a peripheral start of the synucleinopathies, coexisting with cases originating inside the brain [ 152 ].…”

PARK7/DJ-1 in microglia: implications in Parkinson’s disease and relevance as a therapeutic target

“…The large majority of PD cases are idiopathic, meaning that the causes of the disease, which has a sporadic and non-familial appearance, are not known. The onset of PD is associated with environmental risk factors, such as exposure to herbicides and pesticides, brain trauma, infection and chronic stress [18][19][20][21]. However, the most important risk factor for PD is aging.…”