Biology subjects

Slack, R. S.

Publications and source records attributed to Slack, R. S..

4 recordsLinked to original sources

bioRxiv2026

VDAC1 regulates stress-associated matrix localization of DJ-1 to support mitochondrial homeostasis and neuronal survival

DJ-1 is a redox-sensitive protein implicated in early-onset Parkinson's disease, and its mitochondrial localization protects against oxidative stress, but the mechanisms regulating its submitochondrial targeting and functional impact on mitochondrial integrity remain poorly understood. We identify voltage-dependent anion channel 1 (VDAC1) as a regulator of the submitochondrial distribution of DJ-1 during stress. Endogenous DJ-1 interacted with VDAC1, and loss of VDAC1 reduced stress-induced DJ-1 accumulation within the mitochondrial matrix. VDAC1-deficient neurons exhibited mitochondrial fragmentation, impaired oxidative phosphorylation, reduced ATP levels, altered reactive oxygen species (ROS) responses, and increased sensitivity to MPP+;. Matrix-targeted, but not outer-membrane-targeted, DJ-1 rescued basal, ATP-linked, and maximal respiration, improved mitochondrial morphology, and enhanced neuronal survival. ATP synthase inhibition also rapidly increased mitochondrial DJ-1, suggesting bioenergetic stress promotes its mitochondrial accumulation. Our findings identify compartment-specific localization as a key determinant of DJ-1 function and establish VDAC1-dependent matrix targeting as a critical mechanism supporting mitochondrial integrity during stress.

neuroscience↗

bioRxiv2024

Mitotic Activity and DNA Maintenance of Adult Neural Stem Cells is Regulated by Beclin1

Beclin1 is a tumor suppressor gene that can regulate proliferation under pathological conditions. Whether Beclin1 has a role in regulating proliferation in physiological conditions remains unknown. Here, through the creation of an inducible transgenic mouse that removes Beclin1 from adult neural stem and progenitor cells (NSPCs) and their progeny we uncovered that Beclin1 is required cell-autonomously to sustain proliferating NSCPs in vivo and ex vivo. Flow cytometry analysis and single-cell RNA-sequencing show that Beclin1 is required for mitosis. Additional analysis of the proliferating NSPCs resolved by stage of cell cycle uncovered that Beclin1-null cells have a distinct differential developmental trajectory accompanied by downregulation of genes involved in chromosomal maintenance and upregulation of cell stress genes upon cell cycle exit. These effects align with DNA damage in Beclin1-null cells and ultimately result in less adult-born granular neurons. Together these data identify Beclin1 as a novel regulator of mitosis in adult NSPCs.

neuroscience↗

bioRxiv2022

Alterations in neural stem cell quiescence and activation in the 3xTG-AD model of Alzheimers Disease

Alzheimers Disease (AD) is the most common form of dementia with progressive cognitive deficits and mood disorders (Knopman et al., 2021). Recent studies have associated AD pathology with the impairment of adult neurogenesis, as indicated by impaired neural stem cell (NSCs) homeostasis (Bond et al., 2015). Recent work has further associated AD progression with a decline in the number and maturation of adult-born neurons in the SGZ, distinct from typical age-related decline (Moreno-Jimenez et al., 2019). In 3xTG-AD mice, a well-established mouse model of AD, our and other groups have demonstrated impairments to NSC pool and neural progenitor proliferation, as well as adult-born neurons, before the onset of A{beta} plaques and NFTs (Hamilton et al., 2010, 2015; Rodriguez et al., 2008, 2009). However, the regulatory mechanisms underlying the functional impairment of adult NSCs remain to be resolved. Here, we employ single-cell RNA-Seq to establish population-specific defects in the 3xTG-AD mouse model during adult SGZ neurogenesis. Relative to control mice, we observe a dramatic AD-induced decrease in the primed and activated NSC population, which results in a progressive loss of cells committed to neurogenesis. Transcriptome measurements suggest that 3xTG-AD NSCs and their progeny represent enhanced ribosomal and mitochondrial biogenesis, and disturbed Notch signaling pathway. RNA velocity analysis reveals reduced NSC activation as evidenced by a large fraction of Ascl1-postive cells, instead of entering cell cycle, returning to the primed and quiescent state. This is further supported by reduced numbers of Lpar1-expressing cells, a marker of neural progenitor cells, in the SGZ. Our work explores, at a stage-specific resolution, changes in the regulatory networks guiding adult neurogenesis, and identifies niche disturbances in the regulation of NSC quiescence and activation. These NSC deficits underlying impaired neurogenesis identified in AD mice, may be key contributors underlying the compromised hippocampal function in AD.

neuroscience↗

bioRxiv2022

PFTK1 kinase regulates axogenesis during development via RhoA activation.

PFTK1/Eip63E is a member of the Cyclin-dependent kinases (CDKs) family and plays an important role in normal cell cycle progression. Eip63E expresses primarily in postnatal and adult nervous system in Drosophila melanogaster but its role in CNS development remains unknown. We sought to understand the function of Eip63E in the CNS by studying the fly ventral nerve cord during development. Our results demonstrate that Eip63E regulates axogenesis in neurons and its deficiency leads to neuronal defects. Functional interaction studies performed using the same system identify an interaction between Eip63E and the small GTPase Rho1. Furthermore, deficiency of Eip63E homolog in mice, PFTK1, in a newly generated PFTK1 knockout mice results in increased axonal outgrowth confirming that the developmental defects observed in the fly model are due to defects in axogenesis. Importantly, RhoA phosphorylation and activity is affected by PFTK1 in primary neuronal cultures. We here report that GDP bound inactive RhoA is a substrate of PFTK1 and PFTK1 phosphorylation is required for RhoA activity. In conclusion, our work establishes an unreported neuronal role of PFTK1 in axon development mediated by phosphorylation and activation of GDP-bound RhoA. The results presented add to our understanding of the role of Cdks in the maintenance of RhoA mediated axon growth and its impact on CNS development and axonal regeneration.

neuroscience↗