Biological quality control systems eliminate potentially harmful proteins, preventing them from disrupting cellular homeostasis. However, when these control mechanisms are compromised, as in tauopathies such as Alzheimer's disease, misfolded proteins accumulate and contribute to disease pathogenesis.
In a study published in Science last year, Zi-Yang Zhang and colleagues identified the protein TRIM11 as a central regulator of tau aggregation and a potential therapeutic target for neurodegenerative diseases. TRIM proteins are a family of E3 ubiquitin ligases that utilize diverse pathways to degrade both functional and misfolded proteins. Their structural diversity allows individual TRIM proteins to take on specific roles in protein control under physiological and pathophysiological conditions.
In the healthy brain, Tau is a soluble cytoplasmic protein critical for axonal transport, cell communication, and cytoskeletal stability. In contrast, Tau is misfolded in Alzheimer's disease and other tauopathies. It forms insoluble aggregates that disrupt neuronal connections, damage synapses, and promote neuroinflammation.
The authors of the paper have now found that TRIM11 is reduced in Alzheimer's brains. This reduction could be due to genetic variations associated with increased tau pathology and faster disease progression. In cell culture models, TRIM11 had a disaggregating effect on tau aggregates and restored a functional balance between soluble and aggregated tau. When TRIM11 was delivered to the hippocampus or the whole brain of mice (via the cerebrospinal fluid) using an adeno-associated viral vector, it reduced tau pathology and neuroinflammation and improved cognitive and motor performance.
However, TRIM11 also degrades other proteins, such as humanin, a mitochondrial peptide with neuroprotective properties. These effects could attenuate the positive effects of tau aggregate removal. Furthermore, TRIM11 is overexpressed in several cancers, where it promotes the degradation of tumor suppressors such as p53, which correlates with a poorer prognosis. These findings underscore the need for precise regulation of TRIM11 expression in therapeutic applications.
Taken together, TRIM11 shows great potential as a therapeutic target for neurodegenerative diseases, particularly through the regulation of Tau aggregates. At the same time, its complex role in cell biology requires precise and controlled therapeutic application to avoid unwanted side effects.
Reference:
Zhang Z-Y, Harischandra DS, Wang R, Ghaisas S, Zhao JY, McMonagle TP, Zhu G, Lacuarta KD, Song J, Trojanowski JQ, Xu H, Lee VM-Y, Yang X (2023) TRIM11 protects against tauopathies and is down-regulated in Alzheimer's disease. Science 381:eadd6696
Image credit: iStock/Sewcream
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