TRIM11 protects against tauopathies and is down-regulated in Alzheimer’s disease

Abstract

Aggregation of tau into filamentous inclusions underlies Alzheimer’s disease (AD) and numerous other neurodegenerative tauopathies. The pathogenesis of tauopathies remains unclear, which impedes the development of disease-modifying treatments. Here, by systematically analyzing human tripartite motif (TRIM) proteins, we identified a few TRIMs that could potently inhibit tau aggregation. Among them, TRIM11 was markedly down-regulated in AD brains. TRIM11 promoted the proteasomal degradation of mutant tau as well as superfluous normal tau. It also enhanced tau solubility by acting as both a molecular chaperone to prevent tau misfolding and a disaggregase to dissolve preformed tau fibrils. TRIM11 maintained the connectivity and viability of neurons. Intracranial delivery of TRIM11 through adeno-associated viruses ameliorated pathology, neuroinflammation, and cognitive impairments in multiple animal models of tauopathies. These results suggest that TRIM11 down-regulation contributes to the pathogenesis of tauopathies and that restoring TRIM11 expression may represent an effective therapeutic strategy.

BloodDDIT4andTRIM13transcript levels mark the early stages of Machado-Joseph disease

“…62 Tripartite motif (TRIM) family members are crucial players in eliminating misfolded proteins, 63 and some of these proteins have been associated with neurodegenerative diseases, namely TRIM19 in SCA1 34 and TRIM11 in Parkinson’s and Alzheimer diseases. 36,37 Comparing with controls, abundance of blood TRIM13 transcripts was increased in MJD subjects suggesting a peripheral inflammation which may be a reflection of the neuroinflammation found in post-mortem MJD brain. 31,64,65 TRIM13 transcript levels inversely correlated with the expanded CAG repeat in the combined group of Azorean and Brazilian MJD patients, and in the subgroup of early-stage Azorean patients TRIM13 transcript levels inversely correlated with the age of onset.…”

“…After technical validation, a set of genes that maintained the same direction of effect (in at least two comparisons) in relation to the microarray was selected if displaying significant differences ( p <0.05) (n=8), or based on previous data showing that these genes belong to a gene family dysregulated in polyQ diseases (n=4). 31–37 The expression levels of the selected genes (n=12) were then assessed in independent Azorean blood samples from group #2 (Fig. 1C.1).…”

Nucleic Acid Delivery Nanotechnologies for In Vivo Cell Programming

“…This includes intracranially administered AAV5 viral vectors into the brain hippocampus to induce expression of endothelin converting enzyme to degrade amyloid plaques 105 and AAV9 viral vectors that can deliver the TRIM11 gene into the brain to disaggregate tau deposits in mice. 106 The brain is a challenging delivery target due to the blood−brain barrier and the lack of adequate targeting strategies for specific neuronal cell subtypes. 107 Real-time guidance and convection-enhanced delivery strategies can be used in conjunction with improved nucleic acid carrier designs to improve the cell type specificity and spread of the vector throughout the brain for improved efficacy.…”

“…As such, various neuronal cell programming approaches are being developed. This includes intracranially administered AAV5 viral vectors into the brain hippocampus to induce expression of endothelin converting enzyme to degrade amyloid plaques and AAV9 viral vectors that can deliver the TRIM11 gene into the brain to disaggregate tau deposits in mice . The brain is a challenging delivery target due to the blood–brain barrier and the lack of adequate targeting strategies for specific neuronal cell subtypes .…”

An emerging spectrum of therapeutic targets for Alzheimer's disease

“…14 A defect in tau protein quality control and clearance of P-tau is attributable to depressed levels of tripartite motif (TRIM) proteins, especially TRIM11, in AD. 15 As demonstrated in several mouse models of tauopathy, TRIM11 promotes neuronal viability and protects synaptic structure by several mechanisms including enhancing P-tau SUMOylation that leads to its proteosomal degradation, acting as a chaperone for P-tau that prevents misfolding and aggregation, and dissolving P-tau fibrillar deposits. Increasing human brain neuronal levels of TRIM11 could have beneficial effects on AD (Figure 1).…”