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OCIAD1 contributes to neurodegeneration in Alzheimer's disease by inducing mitochondria dysfunction, neuronal vulnerability and synaptic damages.

ABSTRACT: BACKGROUND:Hyperamyloidosis in the brain is known as the earliest neuropathological change and a unique etiological factor in Alzheimer's disease (AD), while progressive neurodegeneration in certain vulnerable brain regions forms the basis of clinical syndromes. It is not clear how early hyperamyloidosis is implicated in progressive neurodegeneration and what factors contribute to the selective brain vulnerability in AD. METHODS:Bioinformatics and experimental neurobiology methods were integrated to identify novel factors involved in the hyperamyloidosis-induced brain vulnerability in AD. We first examined neurodegeneration-specific gene signatures from sporadic AD patients and synaptic protein changes in young transgenic AD mice. Then, we systematically assessed the association of a top candidate gene with AD and investigated its mechanistic role in neurodegeneration. FINDINGS:We identified the ovary-orientated protein OCIAD1 (Ovarian-Carcinoma-Immunoreactive-Antigen-Domain-Containing-1) as a neurodegeneration-associated factor for AD. Higher levels of OCIAD1, found in vulnerable brain areas and dystrophic neurites, were correlated with disease severity. Multiple early AD pathological events, particularly A?/GSK-3? signaling, elevate OCIAD1, which in turn interacts with BCL-2 to impair mitochondrial function and facilitates mitochondria-associated neuronal injury. Notably, elevated OCIAD1 by A? increases cell susceptibility to other AD pathological challenges. INTERPRETATION:Our findings suggest that OCIAD1 contributes to neurodegeneration in AD by impairing mitochondria function, and subsequently leading to neuronal vulnerability, and synaptic damages. FUNDING:Ting Tsung & Wei Fong Chao Foundation, John S Dunn Research Foundation, Cure Alzheimer's Fund, and NIH R01AG057635 to STCW.

SUBMITTER: Li X

PROVIDER: S-EPMC6957876 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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OCIAD1 contributes to neurodegeneration in Alzheimer's disease by inducing mitochondria dysfunction, neuronal vulnerability and synaptic damages.

Li Xuping X Wang Lin L Cykowski Matthew M He Tiancheng T Liu Timothy T Chakranarayan Joshua J Rivera Andreana A Zhao Hong H Powell Suzanne S Xia Weiming W Wong Stephen T C STC

EBioMedicine 20200110

<h4>Background</h4>Hyperamyloidosis in the brain is known as the earliest neuropathological change and a unique etiological factor in Alzheimer's disease (AD), while progressive neurodegeneration in certain vulnerable brain regions forms the basis of clinical syndromes. It is not clear how early hyperamyloidosis is implicated in progressive neurodegeneration and what factors contribute to the selective brain vulnerability in AD.<h4>Methods</h4>Bioinformatics and experimental neurobiology methods ...[more]

PMID: 31931285

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Project description:BackgroundNeurons are highly polarized cells consisting of three distinct functional domains: the cell body (and associated dendrites), the axon and the synapse. Previously, it was believed that the clinical phenotypes of neurodegenerative diseases were caused by the loss of entire neurons, however it has recently become apparent that these neuronal sub-compartments can degenerate independently, with synapses being particularly vulnerable to a broad range of stimuli. Whilst the properties governing the differential degenerative mechanisms remain unknown, mitochondria consistently appear in the literature, suggesting these somewhat promiscuous organelles may play a role in affecting synaptic stability. Synaptic and non-synaptic mitochondrial subpools are known to have different enzymatic properties (first demonstrated by Lai et al., 1977). However, the molecular basis underpinning these alterations, and their effects on morphology, has not been well documented.MethodsThe current study has employed electron microscopy, label-free proteomics and in silico analyses to characterize the morphological and biochemical properties of discrete sub-populations of mitochondria. The physiological relevance of these findings was confirmed in-vivo using a molecular genetic approach at the Drosophila neuromuscular junction.ResultsHere, we demonstrate that mitochondria at the synaptic terminal are indeed morphologically different to non-synaptic mitochondria, in both rodents and human patients. Furthermore, generation of proteomic profiles reveals distinct molecular fingerprints - highlighting that the properties of complex I may represent an important specialisation of synaptic mitochondria. Evidence also suggests that at least 30% of the mitochondrial enzymatic activity differences previously reported can be accounted for by protein abundance. Finally, we demonstrate that the molecular differences between discrete mitochondrial sub-populations are capable of selectively influencing synaptic morphology in-vivo. We offer several novel mitochondrial candidates that have the propensity to significantly alter the synaptic architecture in-vivo.ConclusionsOur study demonstrates discrete proteomic profiles exist dependent upon mitochondrial subcellular localization and selective alteration of intrinsic mitochondrial proteins alters synaptic morphology in-vivo.

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OCIAD1 contributes to neurodegeneration in Alzheimer's disease by inducing mitochondria dysfunction, neuronal vulnerability and synaptic damages.

Publications

OCIAD1 contributes to neurodegeneration in Alzheimer's disease by inducing mitochondria dysfunction, neuronal vulnerability and synaptic damages.

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