In a groundbreaking study published in Schizophrenia (2025), researchers led by Yang, K., Ishizuka, K., and Tomoda, T. have unveiled a previously unrecognized molecular cascade linked to psychotic disorders, bringing new light to the intricate interplay between neurodegeneration and psychiatric illness. This discovery centers on the p62 protein, a key player in autophagy—an essential cellular cleanup process—and its aberrant behavior within olfactory neuronal cells harvested from patients diagnosed with psychosis. The team integrates cutting-edge molecular biology techniques with biopsied human neurons to reveal aging-associated disruptions in autophagic pathways, offering compelling evidence for a biological convergence between aging processes and psychiatric pathology.
The significance of these findings extends beyond schizophrenia or related psychotic disorders alone, touching on fundamental mechanisms that govern cellular homeostasis, neuron integrity, and brain aging. Autophagy, a tightly regulated catabolic process that facilitates the degradation and recycling of damaged cellular components, has long been recognized for its neuroprotective role. However, in psychosis, this protective machinery appears to falter. The p62 protein, known also as sequestosome 1, emerges as a central hub in this dysfunctional cascade. Typically, p62 acts as a selective autophagy receptor, guiding damaged proteins and organelles to autophagosomes for degradation. Its dysregulation, therefore, implicates a breakdown in cellular maintenance that may underlie or exacerbate neuronal deficits observed in psychosis.
Delving into olfactory neuronal cells—a readily accessible but underappreciated window into brain function—the research team harnesses patient-derived biopsies to study this autophagic impairment. Olfactory neurons share many biochemical and physiological traits with central nervous system neurons, and because psychosis frequently correlates with olfactory deficits, these cells represent an ideal proxy for studying disease mechanisms directly from affected individuals. The biopsied cells revealed a conspicuous misregulation of the p62-mediated autophagic flux, a disruption that not only modified intracellular homeostasis but also contributed to protein aggregation and cellular stress, hallmarks commonly observed in neurodegenerative diseases.
Further molecular analyses detailed in the study highlight that this p62 autophagic anomaly is intimately linked with aging-associated molecular events, suggesting that psychosis may co-opt—and possibly accelerate—cellular aging pathways. This intertwining of neuropsychiatric disease with mechanisms traditionally associated with senescence challenges existing paradigms and opens avenues for considering psychosis within a broader framework of age-related cellular dysfunction. The researchers postulate that aberrant p62 function may serve as a molecular switch, triggering autophagic inefficiency that culminates in neuronal vulnerability and altered cognitive and sensory processing seen clinically in psychosis.
Central to understanding this cascade is the observation that disrupted autophagic clearance impairs the removal of aggregated proteins and dysfunctional mitochondria. Both are pivotal contributors to cellular toxicity. Mitochondrial dysfunction, which has already been implicated in the pathology of numerous psychiatric and neurodegenerative conditions, appears exacerbated by failed autophagy. The build-up of damaged mitochondria increases oxidative stress and energy deficits within neurons, potentially accelerating neural deterioration and synaptic dysfunction critical to the clinical manifestation of psychosis. This adds a metabolic dimension to the disease, highlighting a failure of radial cellular quality control mechanisms.
The study’s use of advanced proteomic profiling unveiled how alterations in p62 levels correlate with downstream autophagy-related proteins by mapping comprehensive protein interaction networks within patient-derived neurons. These networks unraveled a cascade effect whereby aging-related signals modify autophagic components at transcriptional and post-translational levels, reinforcing the hypothesis that psychosis pathology encompasses a gradual, molecular wear-and-tear process superimposed upon genetic and environmental risk factors. Such insights pave the way for novel biomarker discovery, enabling earlier detection and patient stratification based on cellular aging profiles.
Intriguingly, the link between olfactory neurons and psychiatric symptoms extends the impact of these findings. Olfactory dysfunctions are among the earliest clinical features noted in psychosis and other neurodegenerative diseases such as Alzheimer’s and Parkinson’s. This research strengthens the notion that olfactory pathways serve as a sensitive sentinel system reflecting deeper neuropathological changes. Impairments in the autophagic clearance mediated by p62 in these peripheral neurons may mirror or even precede central nervous system pathology, presenting new opportunities for minimally invasive diagnostics and intervention monitoring.
Moreover, the study contextualizes the autophagic impairments within a broader framework of proteostasis imbalance, where failure to maintain protein quality control and turnover culminates in toxic accumulation. This imbalance resonates with emerging theories positing that psychiatric diseases, traditionally classified as neurotransmitter imbalances or synaptic disorders, might in fact originate or be exacerbated by fundamental disruptions in cellular maintenance systems. This shift toward viewing psychosis through the lens of cellular aging and proteinopathy could revolutionize therapeutic approaches, moving beyond symptom management to targeting root molecular mechanisms.
In terms of therapeutic implications, modulating autophagy and specifically restoring p62 functionality emerges as a promising strategy. The authors discuss the potential of pharmacological agents or gene therapies aimed at enhancing autophagic flux or correcting p62 dysfunction, which might alleviate neuronal stress and possibly slow or reverse disease progression. Such interventions could also intersect with aging-related treatments, underscoring the need for integrated approaches that address both psychiatric symptoms and underlying cellular degeneration.
The study also innovatively exploits patient-derived neuronal cultures as a platform for testing autophagy-targeted compounds, offering an ex vivo model that more accurately reflects human disease biology compared to traditional animal or immortalized cell models. This can accelerate translational research by enabling drug screening in a personalized context, potentially tailoring treatments to the molecular profiles of individual patients with psychosis associated with autophagic dysfunction.
Beyond its mechanistic revelations, the research prompts a reevaluation of how psychosis is conceptualized in clinical and research communities. Aging is often considered a confounding variable separate from psychiatric pathology; however, this work unveils it as an integral element of disease initiation and progression. Understanding psychosis as overlapping with accelerated cellular aging refines clinical staging models and suggests that interventions may need to be age- and stage-specific to optimize efficacy.
Adding to the narrative, the authors carefully discuss limitations and future directions. While the focus on olfactory neurons provides convenient access, further confirmation in other neuronal populations, especially those implicated in psychosis such as prefrontal cortex or hippocampal neurons, is essential. Longitudinal studies are also paramount to delineate whether p62 autophagic cascade disruption is causal or consequential in disease evolution. Nonetheless, these findings are a crucial stepping stone inviting further exploration into autophagy in psychiatric illness.
From a broader scientific standpoint, this study enriches the growing appreciation for autophagy’s role beyond classical neurodegeneration into the psychiatric realm, forging a link that may unify diverse brain disorders through shared pathways of cellular maintenance failure. It also highlights the utility of multi-omic and patient-derived cellular approaches in uncovering disease mechanisms that are otherwise intractable through traditional methodologies.
This compelling convergence of autophagy, aging, and psychiatric disease not only deepens our molecular understanding of psychosis but also seeds hope for innovative diagnostic and therapeutic avenues. As researchers worldwide grapple with the complexities of mental illness, this work represents a beacon pointing toward the intricate dance of cellular metabolism and neuronal integrity—a dance that, when disrupted, may manifest as the perplexing and devastating symptoms of psychosis.
Ultimately, Yang, Ishizuka, Tomoda, and their colleagues have charted a path that bridges molecular neuroscience and psychiatry, urging the scientific community to rethink aging in the brain not as a mere background process but as a dynamic driver of disease. Their insights underscore a future where cellular quality control, proteostasis, and autophagic regulation are central to unraveling psychiatric illness’s mysteries and designing holistic, mechanistically-grounded treatments.
Subject of Research: Aging-associated p62 autophagic cascade in biopsied olfactory neuronal cells from patients with psychosis
Article Title: Aberrant aging-associated p62 autophagic cascade in biopsied olfactory neuronal cells from patients with psychosis
Article References:
Yang, K., Ishizuka, K., Tomoda, T. et al. Aberrant aging-associated p62 autophagic cascade in biopsied olfactory neuronal cells from patients with psychosis. Schizophr 11, 68 (2025). https://doi.org/10.1038/s41537-025-00617-x
Image Credits: AI Generated
