Biology subjects

Fernandez, M. G.

Publications and source records attributed to Fernandez, M. G..

6 recordsLinked to original sources

bioRxiv2026

Neurodegeneration risk variants promote lysosomal TMEM106B fibrilaccumulation

Variants in TMEM106B and GRN, which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN-mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.

cell biology↗

bioRxiv2025

CTE-Type Tau Filaments in Alzheimer's Disease with Co-morbid LATE-NC

Alzheimers disease (AD), the most common neurodegenerative disease, is defined by {beta}-amyloid plaques and tau neurofibrillary tangles. Tau filaments in AD adopt the "Alzheimers fold", which is distinct from other tauopathies and highly conserved across sporadic and familial AD. However, to date, structural studies have focused on pure AD, despite the high prevalence of comorbid pathologies. In particular, up to half of AD patients harbor limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). This co-pathology-- consisting of mislocalized and aggregated TDP-43, mainly restricted to the medial temporal lobe--is associated with accelerated clinical decline and more severe tau pathology. Whether there is a structural basis for this clinical synergy remains unknown. Here, using cryo-electron microscopy, we determine the structure of tau filaments from three AD patients with LATE-NC. We show that in addition to the expected Alzheimers fold tau filaments, all cases exhibit a distinct fibril morphology identical to chronic traumatic encephalopathy (CTE) fold tau. Additional sampling revealed CTE neuropathology in one patient, suggestive features without definitive CTE in the second, and no evidence of CTE in the third. These findings raise questions about the relationship between LATE-NC and CTE, the effect of TDP-43 on tau conformation, and the etiology of LATE-NC.

molecular biology↗

bioRxiv2024

Endogenous retrovirus-like proteins recruit UBQLN2 to stress granules and alter their functional properties

The human genome is replete with sequences derived from foreign elements including endogenous retrovirus-like proteins of unknown function. Here we show that UBQLN2, a ubiquitin-proteasome shuttle factor implicated in neurodegenerative diseases, is regulated by the linked actions of two retrovirus-like proteins, RTL8 and PEG10. RTL8 confers on UBQLN2 the ability to complex with and regulate PEG10. PEG10, a core component of stress granules, drives the recruitment of UBQLN2 to stress granules under various stress conditions, but can only do so when RTL8 is present. Changes in PEG10 levels further remodel the kinetics of stress granule disassembly and overall composition by incorporating select extracellular vesicle proteins. Within stress granules, PEG10 forms virus-like particles, underscoring the structural heterogeneity of this class of biomolecular condensates. Together, these results reveal an unexpected link between pathways of cellular proteostasis and endogenous retrovirus-like proteins.

neuroscience↗

bioRxiv2024

Molecular Visualization of Neuronal TDP43 Pathology In Situ

Nuclear exclusion and cytoplasmic accumulation of the RNA-binding protein TDP43 are characteristic of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite this, the origin and ultrastructure of cytosolic TDP43 deposits remain unknown. Accumulating evidence suggests that abnormal RNA homeostasis can drive pathological TDP43 mislocalization, thereby enhancing RNA misprocessing due to the loss of nuclear TDP43, and engendering a cycle that ultimately leads to cell death. Here, we demonstrate that the addition of small monovalent oligonucleotides successfully recapitulates pathological TDP43 mislocalization and aggregation, aberrant splicing, and degeneration in iPSC-derived neurons (iNeurons). By employing a tailored multimodal in situ cryo-correlative light and electron microscopy pipeline, we examine the localization and aggregation of TDP43 in near-native conditions. We discover that mislocalized TDP43 accumulates and forms ordered fibrils within autophagosomes and lysosomes in iNeurons, as well as in ALS/FTLD patient tissue. We provide the first high-resolution snapshots of TDP43 aggregates in situ, delivering an unprecedented view of the earliest pathogenic events underlying ALS, FTLD, and related TDP43 proteinopathies.

neuroscience↗

bioRxiv2023

Host metabolic pathways essential for malaria and related hemoparasites in the infection of nucleated cells

Apicomplexan parasite diseases, including malaria (Plasmodium) and theileriosis (Theileria), pose a significant threat to global health and the socioeconomic well-being of low-income countries. Despite recent advances, the common host metabolic proteins essential for these highly auxotrophic pathogens remain elusive. Here, we present a comprehensive investigation integrating a metabolic model of P. falciparum parasites in hepatocytes and a genome-wide CRISPR screen targeting Theileria schizont-infected macrophages. We reveal unifying host metabolic enzymes critical for the intracellular survival of these related hematozoa. We show that pathways such as host purine and heme biosynthesis are essential for both Theileria survival and Plasmodium liver development, while genes involved in glutathione and polyamine biosynthesis are predicted to be essential for Plasmodium only under certain metabolic conditions. Our work highlights the importance of host porphyrins for the viability of liver-stage Plasmodium. Shared parasite vulnerabilities provide a resource for exploring alternative therapeutic approaches to combat these crippling diseases.

microbiology↗

bioRxiv2023

H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours

Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs)1,2. In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as {gamma}H2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA13-6. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours7,8, we identify a novel function for {gamma}H2AX in orchestrating drug-induced replication fork degradation. Mechanistically, {gamma}H2AX-dependent replication fork degradation is elicited by the inhibition of CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection of stalled forks. In summary, our results demonstrate a novel role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair.

cancer biology↗