Biology subjects

Hall, C. M.

Publications and source records attributed to Hall, C. M..

3 recordsLinked to original sources

bioRxiv2025

Reversible synaptic deficits in early-stage Batten disease

Juvenile neuronal ceroid lipofuscinosis (JNCL, Batten Disease) is a childhood-onset, neurodegenerative, lysosomal storage disorder caused by mutations in the lysosomal gene CLN3. Progressive cognitive decline is a key clinical manifestation of JNCL, and no definitive treatment is currently available. The precise function of CLN3 in neurons remains unclear, hindering the development of targeted therapies. Using patch-clamp and AAV-mediated re-expression of CLN3 in Cln3{Delta}ex7/8 mice, we demonstrate that CLN3 is essential for synaptic function. Loss of CLN3 caused defective synaptic vesicle release and reduced synaptic strength reflecting impairments in both pre- and postsynaptic function in Cln3{Delta}ex7/8 mice before the occurrence of neurodegeneration. Moreover, we observed reduced network bursting and deficits in intrinsic neuronal excitability, indicating early functional disturbances independent of storage burden and neuronal death in Cln3-deficient mice. To assess whether CLN3 is required for proper pre- and postsynaptic function, we re-expressed CLN3 selectively in pre- and postsynaptic neurons. We found non-redundant requirements at both pre- and postsynaptic sites to sustain function. Importantly, AAV9-mediated gene rescue at early-disease stages corrected preexisting synaptic defects and restored function. Together, these findings demonstrate the requirement of CLN3 in maintaining synaptic function and show that the therapeutic window may extend to stages characterized by early functional deficits, highlighting the potential of targeted gene therapy to restore function and improve cognitive outcomes.

neuroscience↗

bioRxiv2024

Sodium channel inhibitors alter the progress of tangle development in a mouse model of dementia

Sodium channel inhibitors have been reported to protect against a range of neuroinflammatory and neurodegenerative diseases. Here the effect of chronic administration of two Na+ channel inhibitors with different mechanisms of action, phenytoin and GS967 are tested in mouse models of different stages of Alzheimers disease. Subtle changes in the distribution of plaque sizes were observed in AppNLGF/NLGF mouse at 3 months of age, after being fed control or drug-supplemented chow from weaning onwards, with phenytoin treatment resulting in a significant increase in the frequency of the smallest plaques and a decrease in large plaques. The later pathology of neurofibrillary tangles was studied, in old age, by supplementing the food of transgenic mice with a P301L mutation in Tau. Chronic administration of Na+ inhibitors from 15 months of age resulted in a decrease in the density of MC1-positive neurofibrillary tangles, possibly due to effects on microglial Na+ channels. The density of microglial cells was strongly correlated with the density of neurofibrillary tangles but only in mice treated with the Na+ inhibitors.

neuroscience↗

bioRxiv2019

A cytomegalovirus immunevasin triggers integrated stress response-dependent reorganization of the endoplasmic reticulum.

Human cytomegalovirus (HCMV) encodes an ER-resident glycoprotein, UL148, which activates the unfolded protein response (UPR) but is fully dispensable for viral replication in cultured cells. Hence, its previously ascribed roles in immune evasion and modulation of viral cell tropism are hypothesized to cause ER stress. Here, we show that UL148 is necessary and sufficient to drive the formation of large ER-derived structures that occupy up to 7% of the infected cell cytosol. The structures are found to be sites where UL148 coalesces with cellular proteins involved in ER quality control, such as Hrd1 and EDEM1. Transmission electron microscopy analyses reveal the structures to be comprised of tortuous, densely packed and apparently collapsed ER membranes that connect to distended cisternae. During induced ectopic expression of UL148-GFP fusion protein, punctate signals traffic to accumulate at prominent structures that exhibit poor recovery of fluorescence after photobleaching. Small molecule blockade of the integrated stress response (ISR) prevents the formation of puncta, leading to a uniform reticular fluorescent signal. Accordingly, ISR inhibition during HCMV infection abolishes the coalescence of UL148 and Hrd1 into discrete structures, which argues that UL148 requires the ISR to cause ER reorganization. Given that UL148 stabilizes immature forms of a receptor binding subunit for a viral envelope glycoprotein complex important for HCMV infectivity, our results imply that stress-dependent ER remodeling contributes to viral cell tropism.\n\nIMPORTANCEPerturbations to ER morphology occur during infection with various intracellular pathogens and in certain genetic disorders. We identify that an HCMV gene product, UL148, profoundly reorganizes the ER during infection, and is sufficient to do so when expressed on its own. Our results reveal that UL148-dependent reorganization of the ER is a prominent feature of HCMV infected cells. Moreover, we find that this example of virally induced organelle remodeling requires the integrated stress response (ISR), a stress adaptation pathway that contributes to a number of disease states. Since ER reorganization accompanies the roles of UL148 in HCMV cell tropism and intracellular retention of the immune cell co-stimulatory ligand CD58, our results may have implications for understanding the mechanisms involved. Furthermore, our findings provide a basis to utilize UL148 as a tool to investigate organelle responses to stress and to identify novel drugs targeting the ISR.

microbiology↗