Biology subjects

Penney, J.

Publications and source records attributed to Penney, J..

3 recordsLinked to original sources

bioRxiv2020

A cyclin-dependent kinase 5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes

Aberrant activity of cyclin-dependent kinase (Cdk5) has been implicated in various neurodegenerative diseases. This effect is mediated by pathological cleavage of the Cdk5 activator p35 to produce the truncated product p25, exhibiting increased stability and altered substrate specificity. The benefit of blocking p25 production has been demonstrated in various rodent and human neurodegenerative models. However, important Cdk5/p35 functions in the developing and adult brain have made it challenging to selectively target the detrimental effects of Cdk5/p25 while sparing the physiological functions of Cdk5/p35. Here, we report a 12-amino acid-long peptide fragment derived from Cdk5 (the Cdk5 inhibitory (Cdk5i) peptide) that shows a high binding affinity toward the Cdk5/p25 complex and can efficiently and selectively inhibit Cdk5/p25 kinase activity. Using cellular assays, mouse neurodegeneration models and human cerebral organoids generated from patient-derived iPSCs, we demonstrate beneficial effects of the Cdk5i peptide on various pathological phenotypes including gliosis, DNA damage, and Tau hyperphosphorylation.

neuroscience↗

bioRxiv2020

Probing the functions of microglial cyclin-dependent kinase 5 under physiological and pathological conditions

Cyclin dependent kinase 5 (Cdk5) regulates various developmental and physiological processes in the central nervous system. Deregulation of Cdk5 activity in neurons induces severe neurodegeneration and has been implicated in Alzheimers disease (AD) and other neurodegenerative conditions. A large fraction of AD risk genes are highly expressed in microglia, highlighting an important role for these cells in AD pathogenesis. While Cdk5 function in neurons is well characterized, our understanding of its roles in microglial function under physiological and neurodegenerative conditions remain rudimentary. Here, we investigate the roles of Cdk5 in microglia using myeloid-specific Cdk5 conditional knockout mice. Using microglia-specific transcriptome profiling, histological analyses, and behavioral assessments, we found that knockout of Cdk5 in microglia for 1 month induced transcriptional changes characterized by upregulation of cell cycle processes and type I interferon signaling genes in both physiological conditions and AD-related amyloidogenesis. In contrast to the robust transcriptional changes, conditional loss of microglial Cdk5 produced minimal effects on the density and morphology of microglia and their phagocytic activity toward myelin debris. Moreover, Cdk5cKO mice exhibited little change in synaptic density and tasks associated with locomotor, anxiety-like, and memory-related behaviors. Our findings indicate that the conditional loss of Cdk5 in microglia induces rapid alterations of microglial transcriptome with minimal or delayed effects on histological and behavioral responses.

neuroscience↗

bioRxiv2020

Phosphoproteomics identifies microglial Siglec-F inflammatory response during neurodegeneration

Alzheimers disease (AD) is characterized by the appearance of amyloid-{beta} plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK-p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec-F which was upregulated on a subset of reactive microglia. The human paralog Siglec-8 was also upregulated on microglia in AD. Siglec-F and Siglec-8 were upregulated following microglial activation with interferon gamma (IFN{gamma}) in BV-2 cell line and human stem-cell derived microglia models. Siglec-F overexpression activates an endocytic and pyroptotic inflammatory response in BV-2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine-based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV-2 cells. Collectively, our results point to an important role for mouse Siglec-F and human Siglec-8 in regulating microglial activation during neurodegeneration. HighlightsO_LIPhosphoproteomics analysis of CK-p25, 5XFAD, and Tau P301S mouse models finds dysregulated signaling networks associated with Alzheimers disease pathologies. C_LIO_LIA phosphorylation site on Siglec-F is found to be upregulated across all three models of disease. C_LIO_LIExpression of Siglec-F and its human paralog Siglec-8 is increased in reactive microglia. C_LIO_LIOverexpression of Siglec-F and Siglec-8 in vitro drives an endocytic and pyroptotic inflammatory response. C_LI In BriefPhosphoproteome signaling changes associated with Alzheimers disease (AD) are poorly characterized. Here, Morshed et al. apply phosphoproteomics to mouse models of AD to uncover a novel microglial receptor, Siglec-F, that is upregulated on a subset of inflammatory microglia across models of neurodegeneration. The human paralog, Siglec-8 is also found to be upregulated in late-onset AD microglia. Overexpression of Siglec-F and related human Siglecs activates pro-inflammatory signaling responses in BV-2 cells.

neuroscience↗