Biology subjects

Farias, G.

Publications and source records attributed to Farias, G..

3 recordsLinked to original sources

bioRxiv2026

Calsyntenin-1 and calsyntenin-3 coordinate TGN exit of axonal cargoes

Neurons rely on precise biosynthetic protein transport from the soma to the axon and dendrites. Brain-enriched calsyntenins (CSTN1-3) are unique transmembrane adaptors that link cargo to kinesin-1 for transport. Yet, the neuronal distribution and interdependence of the three CSTN paralogs remain unclear. Here, we dissected their subcellular localization and contribution to biosynthetic protein transport. CSTN paralogs were predominantly localized to the TGN and axonal vesicles, with CSTN1 and CSTN3 showing higher expression levels than CSTN2. Depletion of either CSTN1 or CSTN3 affected axonal abundance of the other, suggesting that they function within the same pathway. Consistently, knockdown of CSTN1 or CSTN3, but not CSTN2, impaired the TGN exit and transport of multiple biosynthetic cargoes to the axon. Interestingly, most CSTN-positive vesicles exiting the TGN and in the axon were marked by the biosynthetic trafficking regulator RAB6A. Furthermore, we identified opposing, paralog-specific roles of CSTN1 and CSTN3 in regulating RAB6A levels at the TGN, thereby contributing to Golgi organization and axonal trafficking. Loss of CSTN1 reduced RAB6A and induced Golgi compaction, whereas loss of CSTN3 increased RAB6A and promoted Golgi dispersal. Together, we reveal that CSTN1 and CSTN3 have distinct, yet intersecting roles in the regulation of biosynthetic axonal transport.

Cell Biology↗

bioRxiv2025

HOPS disruption impairs APP trafficking and processing, promoting exosomal secretion of APP-CTFs

Amyloid precursor protein (APP) is a key player in various neuronal functions but also the source for toxic A{beta} that accumulates in the brain of Alzheimer patients. APP trafficking and processing depend on the endo-lysosomal system, but the molecular mechanisms that coordinate these processes remain unclear. Here, we studied the HOPS complex, a central regulator of endo-lysosomal maturation. We show that HOPS disruption impairs retromer-mediated recycling of APP to the TGN, resulting in the accumulation of APP in late endosomes. In neurons, this accumulation is spatially restricted to somatodendritic endosomes. These APP-containing endosomes are catalytically inactive and lack the {gamma}-secretase subunit PSEN2. However, they do contain BACE1, which leads to the build-up of toxic APP C-terminal fragments (APP-CTFs) upon HOPS disruption. Notably, loss of HOPS enhances secretion of APP-CTFs by exosomes, suggesting a potential mechanism for disease propagation. Together, our findings establish a mechanistic link between HOPS dysfunction and aberrant APP processing, with implications for neurodegeneration. HighlightsO_LIHOPS KO impairs retromer-mediated APP recycling to the TGN C_LIO_LIHOPS disruption redistributes APP to somatodendritic stationary late endosomes C_LIO_LIHOPS depletion increases APP and BACE1 convergence, causing APP-CTF accumulation C_LIO_LIThese APP-CTFs accumulate in catalytically inactive endosomes that lack PSEN2 C_LIO_LIAPP-CTFs are secreted via exosomes, potentially promoting disease propagation C_LI

cell biology↗

bioRxiv2023

Cochlear dysfunction as an early biomarker for cognitive decline in normal hearing and mild hearing loss

Age-related hearing loss (presbycusis) at moderate levels (>40 dB HL) has been recognized as an important risk factor for cognitive decline. However, whether individuals with mild hearing loss (audiogram thresholds between 25 and 40 dB HL) or even those with normal audiograms (<25 dB HL) have a higher risk of dementia, is still debated. Importantly, these early stages of presbycusis are the most common among the elderly, indicating the need to screen and identify individuals with early presbycusis that have an increased risk of cognitive decline. Unfortunately, in this group of patients, audiogram thresholds are not sufficiently sensitive to detect all the hearing impairments that are related to cognitive decline. Consequently, at the individual level, audiogram thresholds are not good estimators of the dementia risk in the group with mild hearing loss or normal hearing thresholds. Here, we propose to use distortion product otoacoustic emissions (DPOAE), as an objective and sensitive tool to estimate the risk of clinically relevant cognitive decline in elders with normal hearing o mild hearing loss. We assessed neuropsychological, brain magnetic resonance imaging, and auditory analyses on 94 subjects aged >64 years old. In addition, cognitive and functional performance was evaluated with the Clinical Dementia Rating Sum of Boxes (CDR SoB), assessed through structured interviews conducted by neurologists, who were blind to the DPOAE results. We found that cochlear dysfunction, measured by DPOAE -and not by conventional audiometry-, was associated with CDR SoB classification and brain atrophy in the group with mild hearing loss (25 to 40 dB), and normal hearing (<25 dB). Our findings suggest that DPOAE may be a non-invasive tool for detecting neurodegeneration and cognitive decline in the elderly, potentially allowing for early intervention.

neuroscience↗