Lim, K.-L. | Search bioRxiv

bioRxiv2020

Hippocampal Transcriptome Profiling Reveals Common Disease Pathways in Chronic Hypoperfusion and Ageing

Vascular dementia (VaD) is a progressive cognitive impairment of vascular etiology. VaD is characterized by cerebral hypoperfusion, increased blood-brain barrier permeability and white matter lesions. An increased burden of VaD is expected due to rapidly aging populations. The hippocampus is particularly susceptible to hypoperfusion, and the resulting memory impairment may play a crucial role in VaD. Here we have investigated the hippocampal gene expression profile of young and old mice subjected to chronic cerebral hypoperfusion by bilateral common carotid artery stenosis (BCAS). Our data in sham-operated young and aged mice show the normal age-associated decline in cerebral blood flow and differential gene expression. BCAS and ageing caused broadly similar effects, however, BCAS-induced changes in hippocampal gene expression differed between young and aged mice. Specifically, transcriptomic analysis indicated that in comparison to young sham mice, many pathways altered by BCAS in young mice resembled those present in sham aged mice. Immunoblot analyses confirmed these findings. Finally, relative to young sham mice the cell type-specific profile of genes in both young BCAS and old sham animals further revealed common cell-specific genes. Our data provide a genetic-based molecular framework for chronic hypoperfusion-induced hippocampal damage and reveal common cellular signaling pathways likely to be important in the pathophysiology of VaD.

neuroscience↗

bioRxiv2020

Parkin coordinates mitochondrial lipid remodeling to execute mitophagy

Mitochondrial failure caused by Parkin mutations contributes to Parkinsons disease. Parkin binds, ubiquitinates, and targets impaired mitochondria for autophagic destruction. Robust mitophagy involves peri-nuclear concentration of Parkin-tagged mitochondria, followed by dissemination of juxtanuclear mitochondrial aggregates, and efficient sequestration of individualized mitochondria by autophagosomes. Here, we report that the execution of complex mitophagic events requires active mitochondrial lipid remodeling. Parkin recruits phospholipase D2 to the depolarized mitochondria and generate phosphatidic acid (PA). Mitochondrial PA is subsequently converted to diacylglycerol (DAG) by Lipin-1 phosphatase-a process that further requires mitochondrial ubiquitination and ubiquitin-binding autophagic receptors, NDP52 and Optineurin. We show that Optineurin transports, via Golgi-derived vesicles, a PA-binding factor EndoB1 to ubiquitinated mitochondria, thereby facilitating DAG production. Mitochondrial DAG activates both F-actin assembly to drive mitochondrial individualization, and autophagosome biogenesis to efficiently restrict impaired mitochondria. Thus Parkin, autophagic receptors and the Golgi complex orchestrate mitochondrial lipid remodeling to execute robust mitophagy.

cell biology↗