Biology subjects

Volbracht, C.

Publications and source records attributed to Volbracht, C..

3 recordsLinked to original sources

bioRxiv2026

BNIP3L/NIX-mediated mitophagy limits Alzheimer disease pathology and preserves neuronal function

Defective mitophagy is emerging as a key contributor to Alzheimer disease (AD), but the neuronal pathways governing mitochondrial clearance and their contribution to disease progression remain poorly understood. Here, we identify BNIP3L/NIX-dependent mitophagy as a conserved neuronal quality control pathway that maintains mitochondrial fitness and constrains AD-associated proteotoxicity. Loss of BNIP3L/NIX or its C. elegans orthologue DCT-1 impaired basal and stressed-induced mitophagy, disrupted mitochondrial homeostasis, enhanced Tau and Amyloid-beta pathology and compromised neuronal network, synaptic and behavioral function across human neuronal and in vivo models. Conversely, restoring BNIP3L/NIX and DCT-1 activity improved neuronal function under proteotoxic stress in vivo, reduced disease-associated Tau phosphorylation in human neurons and markedly suppressed seeded Tau aggregation in primary mouse neurons. Together, these findings identify BNIP3L/NIX-mediated mitophagy as a mechanistic link between mitochondrial quality control, proteostasis and neuronal function, and establish its restoration as a potential strategy for counteracting AD-associated pathology.

cell biology↗

bioRxiv2025

In vivo validation of novel non-invasive PHP.eB AAVs as a potential therapeutic approach for alpha-Synucleinopathies

Parkinsons disease (PD) is characterized by the accumulation of alpha-synuclein (aSyn) aggregates in specific brain regions, which are likely to be the disease-causing entities. Herein, we employed novel, systemically administered, brain-penetrating viral vectors (PHP.eB AAVs) in order to evaluate the potential therapeutic utility of lowering the endogenous aSyn protein burden in the aSyn pre-formed fibril (PFF)-mouse model. Such vectors expressing short hairpin RNAs or micro RNAs targeting the mouse Snca transcript (or respective scrambled control sequences) were intravenously administered in adult wild-type mice and two weeks later human aSyn PFFs were injected into the dorsal striatum. Following the administration of the Snca-targeting PHP.eB AAVs, a successful widespread viral transduction was achieved throughout the brain, accompanied by an efficient reduction of endogenous aSyn protein levels within transduced dopaminergic neurons. Intrastriatal injection of human aSyn PFFs led to the formation of pSer129-aSyn-rich cytoplasmic inclusions in brain regions connected to the PFF-injection site, nigrostriatal degeneration and relevant behavioral motor deficits, at 2.5 months post PFF-injection. Importantly, PHP.eB AAV-mediated down-regulation of endogenous aSyn reduced the accumulation of pSer129-aSyn+ inclusions, mitigated nigrostriatal degeneration and alleviated motor impairments. Spread of pathology to other brain regions was also attenuated. Overall, such data highlight further the contribution of the intracellular aSyn protein load to the spread of pathology and suggest that this non-invasive delivery strategy holds promise in the research avenues for treating neurodegenerative diseases with widespread pathology, such as Synucleinopathies.

neuroscience↗

bioRxiv2022

Visual evoked potentials as an early-stage biomarker in the rTg4510 tauopathy mouse model

Tauopathies such as Alzheimers Disease (AD) and frontotemporal dementia (FTD) are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau protein. Early pathophysiological and functional changes related to neurofibrillary tangles formation are considered to occur prior to extensive neurodegeneration. Hyperphosphorylated tau has been detected in postmortem retinas of AD and FTD patients, and the visual pathway is an easily accessible system in a clinical setting. Hence, assessment of the visual function may offer the potential to detect consequences of early tau pathology in patients. In this study we explored the association between the visual system and functional consequences of tau pathology progression using a tauopathy rTg4510 mouse model. To this end, we recorded full-field electroretinography and visual evoked potentials in anesthetized and awake states at different ages. While retinal function remained mostly intact within all the age groups investigated, we detected significant changes in amplitudes of visual evoked potential responses in young rTg4510 mice exhibiting early tau pathology prior to neurodegeneration. These functional alterations in the visual cortex were positively correlated with pathological tau levels. Our findings suggest that visual processing could be useful as a novel electrophysiological biomarker for early stages of tauopathy.

neuroscience↗