Biology subjects

Coba, M.

Publications and source records attributed to Coba, M..

3 recordsLinked to original sources

bioRxiv2023

Molecular signature and functional properties of human pluripotent stem cell-derived brain pericytes

Brain pericytes maintain the blood-brain barrier (BBB), secrete neurotrophic factors and clear toxic proteins. Their loss in neurological disorders leads to BBB breakdown, neuronal dysfunction, and cognitive decline. Therefore, cell therapy to replace lost pericytes holds potential to restore impaired cerebrovascular and brain functions. However, the molecular composition and function of human iPSC-derived brain pericytes (iPSC-PC) remains poorly characterized. Here, we show by a quantitative analysis of 8,344 proteins and 20,572 phosphopeptides that iPSC-PC share 96% of total proteins and 98% of protein phosphorylation sites with primary human brain pericytes. This includes cell adhesion and tight junction proteins, transcription factors, and different protein kinase families of the human kinome. In pericyte-deficient mice, iPSC-PC home to host brain capillaries to form hybrid human-mouse microvessels with ligand-receptor associations. They repair BBB leaks and protect against neuron loss, which we show requires PDGRFB and pleiotrophin. They also clear Alzheimers amyloid-{beta} and tau neurotoxins in an ex vivo brain slice assay via lipoprotein receptor. Thus, iPSC-PC may have potential as a replacement therapy for pericyte-deficient neurological disorders.

neuroscience↗

bioRxiv2023

Transcript errors generate a continuous stream of amyloid and prion-like proteins in human cells

Aging is characterized by the accumulation of amyloid and prion-like proteins. However, the molecular mechanisms by which these proteins arise remain unclear. Here, we demonstrate that transcript errors generate amyloid and prion-like proteins in a wide variety of human cell types, including stem cells, brain organoids, and fully differentiated neurons. Intriguingly, some of these proteins are identical to proteins previously implicated in familial cases of amyloid diseases, raising the possibility that both familial and non-familial cases are caused by identical mutant proteins. However, transcript errors also generate amyloid proteins that have not been observed before, suggesting that aging cells are exposed to a second class of pathogenic proteins we are currently unaware of. Finally, we show that transcript errors are readily generated by DNA damage, a hallmark of human aging and a staple of multiple proteotoxic diseases, including Alzheimers disease. Together, these observations greatly expand our understanding of mutagenesis in human aging and disease and suggest a new mechanism by which amyloid diseases can develop.

molecular biology↗

bioRxiv2021

Endogenous Syngap1 Alpha Splice Forms Promote Cognitive Function and Seizure Protection

Loss-of-function variants in SYNAGP1 cause a developmental encephalopathy defined by cognitive impairment, autistic features, and epilepsy. SYNGAP1 splicing leads to expression of distinct functional protein isoforms. Splicing imparts multiple cellular functions of SynGAP proteins through coding of distinct C-terminal motifs. However, it remains unknown how these different splice sequences function in vivo to regulate neuronal function and behavior. Reduced expression of SynGAP-1/2 C-terminal splice variants in mice caused severe phenotypes, including reduced survival, impaired learning, and reduced seizure latency. In contrast, upregulation of 1/2 expression improved learning and increased seizure latency. Mice expressing 1-specific mutations, which disrupted SynGAP cellular functions without altering protein expression, promoted seizure, disrupted synapse plasticity, and impaired learning. These findings demonstrate that endogenous SynGAP isoforms with 1/2 spliced sequences promote cognitive function and impart seizure protection. Regulation of SynGAP- expression or function may be a viable therapeutic strategy to broadly improve cognitive function and mitigate seizure.

neuroscience↗