Biology subjects

Hoxha, K.

Publications and source records attributed to Hoxha, K..

3 recordsLinked to original sources

bioRxiv2025

Repositioning of polyubiquitin alters the pathologic tau filament structure

Structurally diverse tau filaments form proteinaceous aggregates in a heterogeneous group of neurodegenerative diseases called tauopathies1. The factors extrinsic to the highly ordered core structure that influence tau filament stability are not well understood. Here, we found that polyubiquitinated tau filaments from Alzheimers disease and vacuolar tauopathy human brain tissue exhibit distinct seeding patterns in mice, in association with differences in tau filament ultrastructure determined by cryo-electron microscopy. Interestingly, chemical modulation of the polarity of polyubiquitin adjacent to the tau core with the small molecule ubistatin B resulted in the repositioning of poorly structured densities towards positively charged residues on the highly structured core filament, leading to shifting of the protofilament-protofilament interface of certain vacuolar tauopathy tau filaments. These results suggest that the structure of tau filaments that are associated with different seeding activities in vivo can be influenced by post-translational modifications.

neuroscience↗

bioRxiv2024

Hyperexcitability precedes CA3 hippocampal neurodegeneration in a dox-regulatable TDP-43 mouse model of ALS-FTD.

Neuronal hyperexcitability is a hallmark of amyotrophic lateral sclerosis (ALS) but its relationship with the TDP-43 aggregates that comprise the predominant pathology in over 90% of ALS cases remains unclear. Emerging evidence in tissue and slice culture models indicate that TDP-43 pathology induces neuronal hyperexcitability suggesting it may be responsible for the excitotoxicity long believed to be a major driver of ALS neuron death. Here, we characterized hyperexcitability and neurodegeneration in the hippocampus of doxycycline-regulatable rNLS8 mice (NEFH-tTA x tetO-hTDP-43{Delta}NLS), followed by treatment with AAV encoded DREADDs and anti-seizure medications to measure the effect on behavioral function and neurodegeneration. We found that approximately half of the CA3 neurons in the dorsal hippocampus are lost between 4 and 6 weeks after TDP-43{Delta}NLS induction. Neurodegeneration was preceded by selective hyperexcitability in the mossy fiber - CA3 circuit, leading us to hypothesize that glutamate excitotoxicity may be a significant contributor to neurodegeneration in this model. Interestingly, hippocampal injection of AAV encoded inhibitory DREADDs (hM4Di) and daily activation with CNO ligand rescued anxiety deficits on elevated zero maze (EZM) but did not reduce neurodegeneration. Therapeutic doses of the anti-seizure medications, valproic acid and levetiracetam, did not improve behavior or prevent neurodegeneration. These results highlight the complexity of TDP-43 - induced alterations to neuronal excitability and suggest that whereas targeting hyperexcitability can meliorate some behavioral deficits, it may not be sufficient to halt or slow neurodegeneration in TDP-43-related proteinopathies. Significance StatementCytoplasmic aggregates of TAR DNA Binding Protein 43 (TDP-43) are the predominant pathology in over 90% of Amyotrophic lateral sclerosis (ALS) and the majority of frontotemporal lobar degeneration (FTLD-TDP) cases. Understanding how TDP-43 pathology promotes neurodegeneration may lead to therapeutic strategies to slow disease progression in humans. Recent reports in mouse and cell culture models suggest loss-of-normal TDP-43 function may drive neuronal hyperexcitability, a key physiological hallmark of ALS and possible contributor to neurodegeneration. In this study, we identified region-specific hyperexcitability that precedes neurodegeneration in the inducible rNLS8 TDP-43 mouse model. Suppressing hyperexcitability with chemogenetics improved behavioral function but did not reduce hippocampal neuron loss. Anti-seizure medications had no beneficial effects suggesting directly targeting hyperexcitability may not be therapeutically effective.

neuroscience↗

bioRxiv2024

ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration

Epigenetic mechanisms, including histone acetylation, are pivotal for learning and memory, with a role in neuronal function in Alzheimers disease and Related Dementia (ADRD). Acetyl-CoA synthetase 2 (ACSS2), an enzyme that generates acetyl-CoA, is central to histone acetylation and gene regulation, particularly in neurons, due to their unique metabolic demands and postmitotic state. ACSS2 can be recruited to the nucleus and chromatin, locally supplying acetyl-CoA to directly fuel histone acetyltransferase enzymes and key neuronal gene expression. This regulatory mechanism may be a promising target for therapeutic intervention in neurodegenerative diseases. Previously we showed that systemic ACSS2 deletion in mice, although largely normal in physiology, is greatly impaired in memory. Here we investigated whether increasing ACSS2 levels could protect neurons against disease and age-associated cognitive decline. Given the role of tau in ADRD, we used primary hippocampal neurons that mimic the sporadic development of tau pathology and the P301S transgenic mouse model for tau-induced memory decline. Our results show that ACSS2 upregulation mitigates tau-induced transcriptional alterations, enhances neuronal resilience against tau pathology, improves long-term potentiation, and ameliorates memory deficits. Expanding upon these findings, we reveal that increasing histone acetylation through ACSS2 upregulation improves age-associated memory decline. These findings indicate that increasing ACSS2 is highly effective in countering age- and tau-induced transcriptome changes, preserving elevated levels of synaptic genes, and safeguarding synaptic integrity. We thus highlight ACSS2 as a key player in the epigenetic regulation of cognitive aging and ADRD, providing a foundation for targeted therapeutics to enhance brain resilience and function. SummaryACSS2 upregulation protects neurons from disease and age-related decline by enhancing synaptic and longevity gene expression.

neuroscience↗