Early Forms of α-Synuclein Pathology Are Associated with Neuronal Complex I Deficiency in the Substantia Nigra of Individuals with Parkinson’s Disease

Idiopathic Parkinson’s disease (iPD) is characterized by degeneration of the dopaminergic substantia nigra pars compacta (SNc), typically in the presence of Lewy pathology (LP) and mitochondrial respiratory complex I (CI) deficiency. LP is driven by α-synuclein aggregation, morphologically evolving from early punctate inclusions to Lewy bodies (LBs). The relationship between α-synuclein aggregation and CI deficiency in iPD is poorly understood. While studies in models suggest they are causally linked, observations in human SNc show that LBs preferentially occur in CI intact neurons. Since LBs are end-results of α-synuclein aggregation, we hypothesized that the relationship between LP and CI deficiency may be better reflected in neurons with early-stage α-synuclein pathology. Using quadruple immunofluorescence in SNc tissue from eight iPD subjects, we assessed the relationship between neuronal CI or CIV deficiency and early or late forms of LP. In agreement with previous findings, we did not observe CI-negative neurons with late LP. In contrast, early LP showed a significant predilection for CI-negative neurons (p = 6.3 × 10−5). CIV deficiency was not associated with LP. Our findings indicate that early α-syn aggregation is associated with CI deficiency in iPD, and suggest a double-hit mechanism, where neurons exhibiting both these pathologies are selectively lost.publishedVersio

The activity of pregnancy-associated plasma protein A (PAPP-A) as expressed by immunohistochemistry in atherothrombotic plaques obtained by aspiration thrombectomy in patients presenting with a ST-elevation myocardial infarction: a brief communication

<p>Abstract</p> <p>Background</p> <p>The expression of pregnancy-associated plasma protein A (PAPP-A) was identified by immunohistochemistry (IHC) in culprit atherothrombotic plaque specimens harvested from patients admitted with ST-segment elevation myocardial infarction (STEMI).</p> <p>Methods</p> <p>The atherothrombotic samples were collected from a consecutive cohort consisting of 20 individuals admitted with STEMI to Stavanger University Hospital, Norway, from 2005-2006, presenting angiographically with an acute thrombotic occlusion of a coronary artery characterized by TIMI flow 0. The atherothrombotic plaques were obtained by aspiration thrombectomy during percutaneous coronary intervention within 12 hours from the onset of symptoms and prepared for IHC analysis.</p> <p>Results</p> <p>In the IHC analysis staining for PAPP-A occurred in the extracellular matrix of the plaques and no evidence of staining for PAPP-A was found in the thrombi.</p> <p>Conclusion</p> <p>Our results indicate that in vivo PAPP-A is strongly expressed in atherothrombotic plaques harvested from patients admitted with STEMI, as documented by IHC.</p> <p>Trial registration</p> <p><email>[email protected]</email></p

Early Forms of α-Synuclein Pathology Are Associated with Neuronal Complex I Deficiency in the Substantia Nigra of Individuals with Parkinson’s Disease

Idiopathic Parkinson’s disease (iPD) is characterized by degeneration of the dopaminergic substantia nigra pars compacta (SNc), typically in the presence of Lewy pathology (LP) and mitochondrial respiratory complex I (CI) deficiency. LP is driven by α-synuclein aggregation, morphologically evolving from early punctate inclusions to Lewy bodies (LBs). The relationship between α-synuclein aggregation and CI deficiency in iPD is poorly understood. While studies in models suggest they are causally linked, observations in human SNc show that LBs preferentially occur in CI intact neurons. Since LBs are end-results of α-synuclein aggregation, we hypothesized that the relationship between LP and CI deficiency may be better reflected in neurons with early-stage α-synuclein pathology. Using quadruple immunofluorescence in SNc tissue from eight iPD subjects, we assessed the relationship between neuronal CI or CIV deficiency and early or late forms of LP. In agreement with previous findings, we did not observe CI-negative neurons with late LP. In contrast, early LP showed a significant predilection for CI-negative neurons (p = 6.3 × 10−5). CIV deficiency was not associated with LP. Our findings indicate that early α-syn aggregation is associated with CI deficiency in iPD, and suggest a double-hit mechanism, where neurons exhibiting both these pathologies are selectively lost

Mitochondrial complex I deficiency stratifies idiopathic Parkinson's disease.

Acknowledgements: We are deeply grateful to the study participants and their families involved in the study for their unique contribution. Furthermore, we would like to thank the entire Park West study consortium for their diligent efforts characterizing and following the Park West cohort; Dr. Yamila Torres Cleuren for the inspirational feedback and critical review of the manuscript; the Neurological Tissue Bank of the IDIBAPS-Hospital Clinic Biobank for providing data and samples; Dr. Brian L Edlow and colleagues for allowing us to use images from their 7 Tesla MRI atlas in Fig. 3; Dr. Romain Guitton, Dr. Kristoffer Haugarvoll and Janani Sundaresan for helping dissect and prepare the brain tissue for RNA-seq; Gry Hilde Nilsen for technical support. This work is supported by grants from The Research Council of Norway (288164; CT), Bergen Research Foundation (BFS2017REK05; CT), The KG Jebsen Foundation (SKGJ-MED-023; CT), and the Western Norway Regional Health Authority (F-10229-D11661; IHF).Idiopathic Parkinson's disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies