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

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. Description Editor’s summary Alzheimer’s disease and more than 20 other dementias and movement disorders collectively known as tauopathies are defined by intracellular filamentous inclusions containing the microtubule-associated protein tau. However, how tau is converted from soluble monomers to insoluble aggregates in these diseases remains unknown. Zhang et al. analyzed more than 70 human tripartite motif (TRIM) proteins and identified several that could reduce tau aggregates (see the Perspective by Noble and Hanger). Among these, TRIM11 was able to maintain tau in its functional soluble form in a manner mechanistically distinct from canonical protein quality control factors. TRIM11 was found to be markedly down-regulated in sporadic Alzheimer’s disease brains, potentially contributing to pathogenesis. Indeed, intracranial adeno-associated viral delivery of TRIM11 provided strong protection against tau pathology, cognitive decline, and motor defects in multiple mouse models of tauopathies. —SMH The TRIM11 protein is down-regulated in Alzheimer’s disease, and restoring its expression may lead to effective therapies. INTRODUCTION Tauopathies encompass Alzheimer’s disease (AD), the most common form of dementia, as well as more than 20 other neurodegenerative disorders. These diseases are pathologically defined by intracellular neurofibrillary tangles (NFTs) composed of the hyperphosphorylated and filamentous form of the microtubule-associated protein tau. It is known that mutations in the tau-encoding gene MAPT cause a heritable subset of tauopathies. However, how tau is converted from soluble monomers to insoluble fibrillar aggregates remains enigmatic. This conspicuous gap in our knowledge hinders the development of mechanism-based therapies for this large group of diseases. RATIONALE In both sporadic and heritable tauopathies, the accumulation of tau aggregates occurs in an age-dependent manner, suggesting that cellular factors could function early in life to inhibit tau misfolding and aggregation. Organisms in all kingdoms of life rely on protein quality control (PQC) systems to remove defective or superfluous normal proteins, to prevent protein misfolding and aggregation, and to dissolve preexisting protein aggregates. Recent studies suggested that tripartite motif (TRIM) proteins, which are found only in metazoans, may participate in multiple aspects of PQC in these highly complex life forms. Here, we investigated the TRIM system to look for its potential role in the pathogenesis of tauopathy, investigate its underlying mechanisms, and test its potential utility as therapeutic agent. RESULTS We examined more than 70 human TRIMs and observed that TRIM10, TRIM55, and especially TRIM11 exhibited a strong ability to remove aggregates formed by a disease-associated tau mutant. An analysis of these three TRIMs in postmortem brain tissue from 23 AD individuals and 14 age- and sex-matched control individuals revealed that the levels of TRIM11 protein, but not mRNA, were substantially reduced in AD brains compared with control brains, whereas the levels of TRIM10 and TRIM55 mRNA and protein levels remained unchanged. Mechanistically, TRIM11 has three activities relevant to tau. First, it mediates the turnover of mutant tau and excess normal tau. It does this by binding to tau, especially the mutant variants or hyperphosphorylated species, and promoting their SUMOylation, leading to their proteasomal degradation. Therefore, TRIM11 represents a crucial link between tau and the proteasome. Second, TRIM11 functions as a molecular chaperone for tau, obviating tau misfolding and aggregation. Third, TRIM11 is a disaggregase for tau, dissolving preexisting tau deposits including the intractable fibrillar aggregates. TRIM11 chaperone and disaggregase activities do not rely on ATP and operate efficiently even at low substoichiometric TRIM11/tau ratios. In various cell models, TRIM11 protects against spontaneous and seeded aggregation of intracellular tau, keeping tau in its functional soluble form. In cultured primary neurons, down-regulation of endogenous TRIM11 impairs, whereas increased expression of TRIM11 promotes, neuronal viability and the formation of presynaptic and postsynaptic puncta. Thus, TRIM11 is an important neuroprotective factor. To examine the role of TRIM11 in the mammalian brain and to evaluate its therapeutic potential, we used multiple mouse models of tauopathy, including PS19 mice, which express the familiar tau mutant P301L; PS19 mice injected with preformed tau fibrils to accentuate disease phenotypes; and 3×Tg-AD mice, which express tau P301L and familial mutations in two AD-related proteins, the amyloid precursor protein and presenilin 1. TRIM11 was delivered through an adeno-associated viral (AAV) vector locally to the hippocampus or globally in the brain through the cerebrospinal fluid. In these models, TRIM11 suppresses tau pathology and neuroinflammation and improves cognitive and motor ability. CONCLUSION These data suggest that TRIM11 plays an important role in protecting against tauopathies and that its down-regulation might contribute to the pathogenesis of these diseases. Our results also highlight a potent, metazoan-specific PQC system with individual components that can perform multiple tasks using mechanisms distinct from those of canonical, ATP-dependent PQC systems. The up-regulation of TRIM11 through small molecules might be feasible given that its expression appears to be highly regulated. Moreover, our findings provide a proof of concept for the TRIM11 gene itself as a therapeutic agent, bolstering PQC capacity and thus addressing the root cause of various neurodegenerative tauopathies. Down-regulation of TRIM11 in AD brains and potential therapeutic benefit of its restoration. (A) TRIM11 expression is inversely correlated with tau pathology. (B) TRIM11 promotes the degradation of mutant and excess normal tau and also functions as a molecular chaperone and a disaggregase, thus enhancing tau solubility. (C) TRIM11 is neuroprotective, and AAV-mediated intracranial delivery of TRIM11 rescues multiple mouse models of tauopathy.