Biology subjects

Bohr, V. A.

Publications and source records attributed to Bohr, V. A..

5 recordsLinked to original sources

bioRxiv2025

Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease

Dysfunctional mitophagy is a key component of Alzheimers disease (AD) pathology, yet direct in vivo evidence and mechanistic insights remain limited. Using a mitophagy reporter in an AD mouse model (APP/PSEN1/mt-Keima), we identified mitochondrial plaques (MPs) composed of accumulated mitochondria within or outside lysosomes in AD, but not normal mouse brains. Similar structures were also found in AD human brains, but not in healthy controls. Abnormal mitochondrial accumulation in dystrophic neurites, defective mitophagy, and impaired lysosomal function disrupted proper mitochondrial degradation, resulting in excessive mitochondria accumulation both within and outside autophagic vesicles. The resulting intensive mitochondria-containing neurites coalesce into MPs, which co-develop with amyloid plaques to form mixed plaques. These findings establish MPs as novel pathological entity and a promising therapeutic target in AD.

cell biology↗

bioRxiv2024

Urolithin A improves Alzheimers disease cognition and restores mitophagy and lysosomal functions

BackgroundCompromised autophagy, including impaired mitophagy and lysosomal function, is thought to play a pivotal role in Alzheimers disease (AD). Urolithin A (UA) is a gut microbial metabolite of ellagic acid that stimulates mitophagy. The effects of early and/or long-term treatment, as well as more detailed mechanisms of action, are not known. MethodsWe addressed these questions in three mouse models of AD, and behavioral, electrophysiological and biochemistry assays were performed. ResultsLong-term UA treatment significantly improved learning, memory and olfactory function in different AD transgenic mice. UA also reduced A{beta} and Tau pathologies, and improved long-term potentiation. We found that UA activated autophagy/mitophagy via increasing lysosomal functions. At the cellular level, UA improved lysosomal function and normalized lysosomal cathepsins, especially targeting cathepsin Z, to restore lysosomal function in AD, indicating the important role of cathepsins in UA-induced therapeutic effects of AD. ConclusionsCollectively, our study highlights the importance of lysosomal dysfunction in AD etiology, and points to the high translational potential of UA.

neuroscience↗

bioRxiv2022

Long-term NAD+ supplementation prevents the progression of age-related hearing loss in mice

Age-related hearing loss (ARHL) is the most common sensory disability associated with human aging. Yet, there are no approved measures for preventing or treating this debilitating condition. With its slow progression, continuous and safe approaches are critical for ARHL treatment. Nicotinamide Riboside (NR), a NAD+ precursor, is well tolerated even for long-term use and is already shown effective in various disease models including Alzheimers and Parkinsons Disease. It has also been beneficial against noise induced hearing loss and in hearing loss associated with premature aging. However, its beneficial impact on ARHL is not known. Using two different wild-type mouse strains, we show that long-term NR administration prevents the progression of ARHL. Through transcriptomic and biochemical analysis, we find that NR administration restores age-associated reduction in cochlear NAD+ levels, upregulates biological pathways associated with synaptic transmission and PPAR signaling, and reduces the number of orphan ribbon synapses between afferent auditory neurons and inner hair cells. We also find that NR targets a novel pathway of lipid droplets in the cochlea by inducing the expression of CIDEC and PLIN1 proteins that are downstream of PPAR signaling and are key for lipid droplet growth. Taken together, our results demonstrate the therapeutic potential of NR treatment for ARHL and provide novel insights into its mechanism of action.

animal behavior and cognition↗

bioRxiv2020

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling

BackgroundCockayne syndrome (CS) is a rare premature aging disease, most commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and have an average life expectancy of 12 years. The CS proteins are involved in transcription and DNA repair, with the latter including transcription-coupled nucleotide excision repair (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, which likely contributes to the severe premature aging phenotype of this disease. While damaged mitochondria and impaired mitophagy were characterized in mice with CSB deficiency, such changes in the CS nematodes and CS patients are not fully known. ResultsOur cross-species transcriptomic analysis in CS postmortem brain tissue, CS mouse and nematode models show that mitochondrial dysfunction is indeed a common feature in CS. Restoration of mitochondrial dysfunction through NAD+ supplementation significantly improved lifespan and healthspan in the CS nematodes, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. In cerebellar samples from CS patients, we found molecular signatures of dysfunctional mitochondrial dynamics and impaired mitophagy/autophagy. In primary cells depleted for CSA or CSB, this dysfunction can be corrected with NAD+ supplementation. ConclusionsOur study provides support for the interconnection between major causative aging theories, DNA damage accumulation, mitochondrial dysfunction, and compromised mitophagy/autophagy. Together these three agents contribute to an accelerated aging program that can be averted by NAD+ supplementation.

cell biology↗

bioRxiv2019

Self-assembly of multi-component mitochondrial nucleoids via phase separation

Mitochondria contain an autonomous and spatially segregated genome. The organizational unit of their genome is the nucleoid, which consists of mitochondrial DNA (mtDNA) and associated architectural proteins. Here, we show that phase separation is the primary physical mechanism for assembly and size-control of the mitochondrial nucleoid. The major mtDNA-binding protein TFAM spontaneously phase separates in vitro via weak, multivalent interactions into viscoelastic droplets with slow internal dynamics. In combination, TFAM and mtDNA form multiphase, gel-like structures in vitro, which recapitulate the in vivo dynamic behavior of mt-nucleoids. Enlarged, phase-separated, yet transcriptionally active, nucleoids are present in mitochondria from patients with the premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS) and are associated with mitochondrial dysfunction. These results point to phase separation as an evolutionarily conserved mechanism of genome organization. HighlightsO_LIMitochondrial genomes are organized by phase separation. C_LIO_LIThe main packaging protein TFAM and mtDNA combine to form viscoelastic, multiphase droplets in vitro. C_LIO_LIMitochondrial nucleoids exhibit phase behavior in vivo, including dynamic rearrangements and heterogenous organization. C_LIO_LICoalescence and enlargement of mt-nucleoids occur upon loss of mitochondrial homeostasis as well as in prematurely aged cells and are associated with mitochondrial dysfunction. C_LI

cell biology↗