Biology subjects

Goldberg, M. S.

Publications and source records attributed to Goldberg, M. S..

3 recordsLinked to original sources

bioRxiv2024

Alpha-synuclein preformed fibril-induced aggregation and dopaminergic cell death in cathepsin D overexpression and ZKSCAN3 knockout mice

-synuclein accumulation is recognized as a prominent feature in the majority of Parkinsons disease cases and also occurs in a broad range of neurodegenerative disorders including Alzheimers disease. It has been shown that -synuclein can spread from a donor cell to neighboring cells and thus propagate cellular damage, antagonizing the effectiveness of therapies such as transplantation of fetal or iPSC derived dopaminergic cells. As we and others previously have shown, insufficient lysosomal function due to genetic mutations or targeted disruption of cathepsin D can cause -synuclein accumulation. We here investigated whether overexpression of cathepsin D or knockout (KO) of the transcriptional suppressor of lysosomal biogenesis ZKSCAN3 can attenuate propagation of -synuclein aggregation and cell death. We examined dopaminergic neurodegeneration in the substantia nigra using stereology of tyrosine hydroxylase-immunoreactive cells 4 months and 6 months after intrastriatal injection of -synuclein preformed fibrils or monomeric -synuclein control in control, central nervous system (CNS)-cathepsin D overexpressing and CNS-specific ZKSCAN3 KO mice. We also examined pS129--synuclein aggregates in the substantia nigra, cortex, amygdala and striatum. The extent of dopaminergic neurodegeneration and pS129--synuclein aggregation in the brains of CNS-specific ZKSCAN3 knockout mice and CNS-cathepsin D overexpressing mice was similar to that observed in wild-type mice. Our results indicate that neither enhancing cathepsin D expression nor disrupting ZKSCAN3 in the CNS is sufficient to attenuate pS129--synuclein aggregate accumulation or dopaminergic neurodegeneration.

neuroscience↗

bioRxiv2024

Alterations of PINK1-PRKN signaling in mice during normal aging

The ubiquitin kinase-ligase pair PINK1-PRKN identifies and selectively marks damaged mitochondria for elimination via the autophagy-lysosome system (mitophagy). While this cytoprotective pathway has been extensively studied in vitro upon acute and complete depolarization of mitochondria, the significance of PINK1-PRKN mitophagy in vivo is less well established. Here we used a novel approach to study PINK1-PRKN signaling in different energetically demanding tissues of mice during normal aging. We demonstrate a generally increased expression of both genes and enhanced enzymatic activity with aging across tissue types. Collectively our data suggest a distinct regulation of PINK1-PRKN signaling under basal conditions with the most pronounced activation and flux of the pathway in mouse heart compared to brain or skeletal muscle. Our biochemical analyses complement existing mitophagy reporter readouts and provide an important baseline assessment in vivo, setting the stage for further investigations of the PINK1-PRKN pathway during stress and in relevant disease conditions.

neuroscience↗

bioRxiv2018

Precisely control mitochondrial membrane potential with light to manipulate cell fate decisions

Mitochondrial dysfunction has been implicated in many pathological conditions and diseases. The normal functioning of mitochondria relies on maintaining the inner mitochondrial membrane (IMM) potential (a.k.a. {Delta}{Psi}m) that is essential for ATP synthesis, Ca2+ homeostasis, redox balance and regulation of other key signaling pathways such as mitophagy and apoptosis. However, the detailed mechanisms by which {Delta}{Psi}m regulates cellular function remain incompletely understood, partially due to difficulty of manipulating {Delta}{Psi}m with spatiotemporal resolution, reversibility, or cell type specificity. To address this need, we have developed a next-generation optogenetic-based technique for controllable mitochondrial depolarization with light. We demonstrate successful targeting of the heterologous Channelrhodopsin-2 (ChR2) fusion protein to the IMM and formation of functional cationic channels capable of light-induced selective {Delta}{Psi}m depolarization and mitochondrial autophagy. Importantly, we for the first time show that optogenetic-mediated mitochondrial depolarization can be well-controlled to differentially influence the fate of cells expressing mitochondrial ChR2: while sustained moderate light illumination induces substantial apoptotic cell death, transient mild light illumination elicits cytoprotection via mitochondrial preconditioning. Finally, we show that Parkin overexpression exacerbates, instead of ameliorating, mitochondrial depolarization-mediated cell death in HeLa cells. In summary, we provide evidence that the described mitochondrial-targeted optogenetics may have a broad application for studying the role of mitochondria in regulating cell function and fate decision.

cell biology↗