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Proteomic characterization of neuromelanin granules and substantia nigra in health and disease

ABSTRACT: Neuromelanin is a black-brownish pigment, present in so-called neuromelanin granules (NMG) in the cell bodies of dopaminergic neurons in the substantia nigra. These neurons are lost in neurodegenerative diseases like Parkinson’s disease and dementia with Lewy bodies (DLB). Although it is known that lipids, proteins, and environmental toxins accumulate in NMG, the function of NMG in health and disease remains elusive, as well as the synthesis of neuromelanin. We therefore isolated NMG and surrounding SN tissue from control and DLB patients by laser micro-dissection and analyzed the proteomic profile by tandem-mass spectrometry. The NMG core proteome consisted of several proteins specific for stress granules regardless of health status, indicating a potential, yet unknown, association of NMG and stress granules. Potential-disease related proteomic alterations lead us to the hypothesis of an eventual impairment of the lipid metabolism, as associated proteins were lower abundant in SN tissue of DLB patients. Furthermore, α-synuclein was found to be specifically higher abundant in NMG of DLB patients. As α-synuclein is known to form neurotoxic aggregates, the accumulation inside of NMG suggests a neuroprotective role of NMG in synucleinopathies. With our results, we are able to propose alternative hypotheses on NMG origin and function.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Lewy Body Dementia

SUBMITTER: Britta Eggers

LAB HEAD: Katrin Marcus

PROVIDER: PXD025643 | Pride | 2021-06-07

REPOSITORIES: Pride

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Project description:Dementia with Lewy bodies (DLB) is the second most common cause of degenerative dementia after Alzheimer’s disease (AD) and presents several overlapping pathological and clinical features with both AD and Parkinson’s disease (PD). Consequently, only one in three DLB cases is diagnosed correctly. Platelets are anucleate cells containing cellular structures and molecules, such as microRNA (miRNA), the analysis of which provides biomarkers for several disorders. In this cross-sectional study, we profiled the whole platelet miRNA transcriptome from 7 DLB patients and 7 healthy controls using Next-Generation Sequencing (NGS) and found 22 differentially expressed miRNAs. These miRNAs were further validated with miRCURY LNA miRNA Custom PCR panels in three consecutive validation studies carried out from 2017-2019 with a total of 162 individuals including DLB (n=59), AD (n=28), and PD patients (n=24), and healthy controls (n=51). As a result, three different groups of miRNAs were identified as related to DLB, AD and PD, all in comparison with controls. Additionally, our results demonstrated a significant down-regulation of hsa-miR-26b-5p and hsa-miR-150-5p in DLB compared to PD; and a signature composed of seven miRNAs that had lower expression in DLB compared to AD. The predictive diagnostic value of this bio-signature for the differentiation of DLB from AD was assessed calculating the corresponding ROC curve, which yielded an area under the curve of 1.00. Predictive analyses using specialized software (miRTarbase, miRGate) were performed for the disease-specific miRNAs to identify target genes and corresponding pathways. Three disease-specific clusters of pathways and biological processes were identified as a result of platelet-miRNA deregulation. In DLB, pathways related to gene expression and small RNA metabolism; in AD, pathways related to stress response and RNA stress granules; and in PD pathways related to protein phosphorylation, and protein metabolism and degradation were identified. In conclusion, we describe the identification of a novel, highly specific and sensitive platelet-associated miRNA-based bio-signature, which permits us to distinguish between DLB and AD.

			Action	DRS
	FLI06523.mzML	Mzml
	FLI06523.raw	Raw
	FLI06525.mzML	Mzml
	FLI06525.raw	Raw
	FLI06527.mzML	Mzml

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Proteomic characterization of neuromelanin granules and substantia nigra in health and disease

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