A groundbreaking study published in 2025 sheds new light on the molecular underpinnings of Parkinson’s disease, revealing how the deficiency of the triggering receptor expressed on myeloid cells 2 (TREM2) amplifies cognitive decline via enhanced lysosomal dysfunction triggered by pathological α-Synuclein accumulation. This research, conducted by Zhu, Feng, Liang, and colleagues, brings to the forefront critical cellular mechanisms that may redefine therapeutic strategies for one of the most challenging neurodegenerative disorders worldwide.
The crux of Parkinson’s disease pathology involves the misfolding and aggregation of α-Synuclein, a presynaptic neuronal protein implicated in synaptic dysfunction and neurodegeneration. While the accumulation of toxic α-Synuclein species in the brain has long been identified as a hallmark of the disease, the precise pathways connecting this proteinopathy to cognitive impairment have remained elusive. The current study pioneers the understanding of how α-Synuclein fosters lysosomal deficits, a crucial cellular waste disposal system, and how TREM2 functions within this context.
TREM2, a receptor predominantly expressed on microglia, represents a key player in immune surveillance and phagocytic clearance within the central nervous system. Previous research has documented TREM2’s role in Alzheimer’s disease, but its involvement in Parkinson’s disease-related cognitive dysfunction marks a novel area of investigation. By interrogating the impact of TREM2 deficiency on α-Synuclein pathology, Zhu and colleagues provide compelling evidence for TREM2’s protective function against lysosomal impairment.
Lysosomes serve as the cellular waste disposers, responsible for degrading and recycling damaged proteins and organelles. Dysfunctional lysosomal pathways are increasingly recognized as central contributors to neurodegeneration, as they hinder effective clearance of toxic protein aggregates, allowing pathological species to accumulate and propagate. This study elegantly demonstrates that TREM2 deficiency aggravates α-Synuclein-induced lysosomal malfunction, disrupting neuronal homeostasis and accelerating cognitive decline.
Utilizing advanced molecular biology techniques and sophisticated in vivo models mimicking Parkinson’s disease pathology, the research team meticulously quantified the extent of lysosomal disruption in the presence and absence of functional TREM2. Their findings reveal a marked exacerbation of lysosomal deficits when TREM2 is deficient, underscoring the receptor’s critical role in maintaining lysosomal integrity amid α-Synuclein stress.
Furthermore, the investigation delves into the downstream cellular consequences of impaired lysosomal function, highlighting increased oxidative stress, neuroinflammation, and synaptic damage—key pathological features that culminate in cognitive deterioration. The interplay between TREM2 signaling and these neurodegenerative cascades suggests that enhancing TREM2 function could mitigate multiple facets of disease progression.
The study also explores the molecular signaling pathways modulated by TREM2 under conditions of α-Synuclein overload. Activation of TREM2 triggers intracellular cascades that boost microglial phagocytic capacity and promote lysosomal biogenesis. Loss of TREM2 impairs these protective responses, tipping the balance towards neurotoxicity. This mechanistic insight has profound implications for developing microglia-targeted therapies aiming to restore lysosomal competence.
Cognitive impairment in Parkinson’s disease, often overshadowed by the more prominent motor symptoms, profoundly diminishes quality of life. The identification of TREM2’s pivotal role offers hope for therapeutic interventions specifically addressing the cognitive domain. Enhancing TREM2 activity or mimicking its downstream effects could constitute innovative strategies to preserve cognitive function in patients.
In light of these findings, the authors propose a model in which TREM2 deficiency creates a vicious cycle: α-Synuclein accumulation impairs lysosomal function, diminishing the ability of microglia to clear pathological proteins, which in turn fosters further α-Synuclein aggregation and neurodegeneration. Interrupting this cycle by restoring TREM2 function may represent a promising therapeutic avenue.
The implications of this research extend beyond Parkinson’s disease. Given the shared mechanisms of protein aggregation and lysosomal dysfunction across various neurodegenerative diseases, understanding TREM2’s role could inform broader neuroprotective strategies. It opens new avenues for biomarker development, diagnostic imaging, and precision medicine tailored to microglial genetic profiles.
From a translational perspective, pharmacological agents or gene therapies designed to potentiate TREM2 signaling are now poised for rigorous preclinical evaluation. The detailed mechanistic insights provided by Zhu et al. offer a roadmap to target microglial lysosomal pathways and potentially delay or reverse cognitive decline.
Importantly, the study employs cutting-edge imaging and biochemical assays to monitor lysosomal activity and α-Synuclein dynamics in real time, allowing for a nuanced understanding of temporal disease progression. This technological advancement enhances the reliability of data and paves the way for future longitudinal studies in patients.
While this research marks a significant leap forward, the authors emphasize the need for further investigation into how TREM2 interacts with other cellular pathways contributing to neurodegeneration. Identifying potential compensatory mechanisms and understanding intercellular crosstalk will be crucial to fully harness TREM2’s therapeutic potential.
The robust experimental design, including the use of both genetic knockout models and human patient-derived cells, strengthens the validity of the findings. Such comprehensive approaches underscore the pivotal role of TREM2 in maintaining lysosomal function and cognitive integrity within the Parkinsonian brain.
As the neurological community considers this new data, it is clear that targeting microglial biology and lysosomal health addresses a fundamental disease axis. This study catalyzes a paradigm shift, advocating for combined therapeutic approaches that modulate immune and proteostatic pathways simultaneously.
In conclusion, Zhu and colleagues have unraveled a critical piece of the Parkinson’s disease puzzle by demonstrating that TREM2 deficiency exacerbates cognitive impairment through the aggravation of α-Synuclein-induced lysosomal dysfunction. Their insightful work not only enlightens disease pathogenesis but also charts promising paths for innovative therapies aimed at combating neurodegeneration and preserving cognitive function in afflicted individuals.
Subject of Research: The role of TREM2 deficiency in exacerbating cognitive impairment via lysosomal dysfunction induced by α-Synuclein in Parkinson’s disease.
Article Title: TREM2 deficiency exacerbates cognitive impairment by aggravating α-Synuclein-induced lysosomal dysfunction in Parkinson’s disease.
Article References:
Zhu, B., Feng, J., Liang, X. et al. TREM2 deficiency exacerbates cognitive impairment by aggravating α-Synuclein-induced lysosomal dysfunction in Parkinson’s disease. Cell Death Discov. 11, 243 (2025). https://doi.org/10.1038/s41420-025-02538-1
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41420-025-02538-1
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