Abstract
Subjects with incidental Lewy body disease (iLBD) may represent the premotor stage of Parkinson’s disease (PD). To elucidate molecular mechanisms underlying neuronal dysfunction and alpha-synuclein pathology in the premotor phase of PD, we investigated the transcriptome of the substantia nigra (SN) of well-characterized iLBD, PD donors and age-matched controls with Braak alpha-synuclein stage ranging from 0–6. In Braak alpha-synuclein stages 1 and 2, we observed deregulation of pathways linked to axonal degeneration, immune response and endocytosis, including axonal guidance signaling, mTOR signaling, EIF2 signaling and clathrin-mediated endocytosis in the SN. In Braak stages 3 and 4, we observed deregulation of pathways involved in protein translation and cell survival, including mTOR and EIF2 signaling. In Braak stages 5 and 6, we observed deregulation of dopaminergic signaling, axonal guidance signaling and thrombin signaling. Throughout the progression of PD pathology, we observed a deregulation of mTOR, EIF2 and regulation of eIF4 and p70S6K signaling in the SN. Our results indicate that molecular mechanisms related to axonal dysfunction, endocytosis and immune response are an early event in PD pathology, whereas mTOR and EIF2 signaling are impaired throughout disease progression. These pathways may hold the key to altering the disease progression in PD.
Highlights
Substantial dopaminergic cell loss in the substantia nigra (SN) is considered to be the pathoanatomical substrate of the motor symptoms in Parkinson’s disease (PD) [1]
When we focus on the anterograde transporter proteins, we observed a down regulation of kinesin light chain (KLC) (p = 0.02, FC = -1.42) and kinesin family 20A (KIF20A) (p = 0.02, FC = -1.17) in Braak alpha-synuclein stage 1–2 compared to controls
The transcriptome of post-mortem SN tissue of donors with Braak alpha-synuclein stages 0 to 6 revealed a consistent deregulation of pathways related to macroautophagy and protein synthesis, including EIF2 signaling, mTOR signaling and regulation of eIF4 and p70S6K signaling during the progression of PD pathology
Summary
Substantial dopaminergic cell loss in the substantia nigra (SN) is considered to be the pathoanatomical substrate of the motor symptoms in Parkinson’s disease (PD) [1]. The alpha-synuclein pathology in PD is not limited to the SN, but observed in many brain regions [3,4,5,6]. It has been postulated that the alpha-synuclein pathology in the brain starts in the lower brainstem and advances to the limbic and neocortical brain regions during progression of the disease [6,7,8]. Alpha-synuclein pathology and nigrostriatal loss have been observed in aged individuals without evidence of Parkinsonism or dementia during life [9, 10] and are defined pathologically as incidental Lewy Body (iLBD) subjects, suggesting that these subjects may represent the premotor stage of PD [11,12,13,14]. Studying post-mortem SN tissue of iLBD subjects may, provide insight into molecular mechanisms involved in alpha-synuclein aggregation and neuronal dysfunction in early stage PD and shed light on its pathogenesis
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