Gene expression changes likely mediate the impact of Alzheimer’s disease (AD) neuropathology on cognition, but there are challenges to resolve the proximal causal pathways from postmortem brain transcriptome profiles which lack temporal resolution and are further confounded by mixed pathologies. Here, we functionally dissect 30 AD-associated human brain gene co-expression modules using fruit fly (Drosophila melanogaster) models. Integrating longitudinal RNA-sequencing and behavioral phenotyping, we interrogated the consequences of amyloid beta (Aβ) plaques, tau neurofibrillary tangles, and aging, highlighting hundreds of conserved, differentially expressed genes. To pinpoint causal modules and drivers, we manipulated 344 prioritized targets in vivo, identifying 141 modifiers of Aβ- or tau-induced neurodegeneration. We discovered an upregulated immune module enriched for AD risk variants that promotes neurodegeneration based on genetic manipulations in neurons. By contrast, a downregulated human brain synaptic regulatory network includes many loss-of-function suppressors of Aβ/tau and modulates glutamatergic hyperexcitation injury. Additional analyses support a biphasic model in which early AD pathology activates expression of a synaptic transcriptional signature that promotes neuronal injury, followed by a decrease that is compensatory. In sum, our cross-species strategy establishes a causal chain linking AD pathology, transcriptome perturbation, N-Methyl-D-Aspartate receptor excitotoxicity, and neurodegeneration.

Neurons adapt gene expression to counter aging, yet the mechanisms by which they harness age- related genes to resist neurodegenerative disease remain elusive. We found that transcriptionalaging inversion (TAGI) in the Drd1 -expressing striatal neurons ( Drd1 SNs) of Huntington's disease (HD) knock-in ( Hdh ) mice exhibits discrete patterns against a TAG-like (TAGL) signature. Strikingly, TAGI dynamics may explain disease progression more accurately than TAGL. Moreover, in Drd1 SNs, genes affected by 3'UTR accumulation during aging are predisposed to downregulation in aging and deregulation in Hdh mice. By integrating age-related 3'UTR data and Hdh -mice data, we identified a CAG-repeat-dependent network of upregulated genes with compensatory potential. This network features (i) Atad-5, a P CNA unloader that modifies CAG expansion in human HD plasma samples, and (ii) CXXC4 (IDAX), an epigenetic regulator whose early-stage upregulation is lost as behavioral symptoms worsen in Hdh mice. Functionally, CXXC4 reduces the senescence marker p16INK4a and restores glutamate excitability in human HD iPS cell-derived SNs. Collectively, these findings suggest that Drd1 SN resilience capacity against HD relies on discrete age-related patterns and responses transiently activated in early disease stages. The reactivation of specific age-related genes such as CXXC4 may notably restore cortico-striatal function in HD.

X-linked adrenoleukodystrophy (X-ALD) is a progressive neurodegenerative disorder caused by a loss-of-function (LOF) mutation in the ATP-binding cassette subfamily D member 1 (ABCD1) gene, leading to the accumulation of very long-chain fatty acids (VLCFAs). This disorder exhibits striking heterogeneity; some male patients develop an early childhood neuroinflammatory demyelination disorder, while other patients, including adult males and most affected female carriers, experience a chronic progressive myelopathy. Adrenocortical failure is observed in almost all male patients, with the age of onset varying, sometimes being the first diagnostic finding. The gene underlying this spectrum of disease encodes an ATP-binding cassette (ABC) transporter that localizes to peroxisomes and facilitates VLCFA transport. X-ALD is considered a single peroxisomal component defect and does not play a direct role in peroxisome assembly. Drosophila models of other peroxisomal genes have provided mechanistic insight into some of the neurodegenerative mechanisms with reduced lifespan, retinal degeneration, and VLCFA accumulation. Here, we perform a genetic analysis of the fly ortholog Abcd1 (CG2316). Knockdown or knockout of Abcd1 leads to salivary gland defects, reduced peroxisomal abundance, and VLCFA accumulation. Our null model further highlights locomotor impairment and lifespan abnormalities. Flies overexpressing the human cDNA for ABCD1, but not the fly Abcd1, display a wing crumpling phenotype characteristic of the Pex2 loss-of-function. Taken together, our data establishes the loss-of-function phenotypes for Abcd1 in Drosophila, which resemble X-ALD pathology, and suggests that overexpression of human ABCD1 may act as an inhibitor of peroxisomal biogenesis in flies. This fly model provides valuable insight into disease mechanisms and offers a versatile platform to model cerebral ALD, functionally resolve ABCD1 variants by their capacity to mitigate the biogenesis defect, assess the restorative potential of candidate small molecules, and enable discovery for this important disease.

Parkinson's disease (PD), the most common neurodegenerative movement disorder, imposes a growing healthcare and socioeconomic burden worldwide. A defining hallmark of PD is the accumulation of α-synuclein (αSyn) within intracellular inclusions such as Lewy bodies and Lewy neurites. Genomic studies have identified numerous PD risk factors within the endolysosomal pathway (ELP), an essential cellular system for protein and membrane recycling. Concordantly, recurrent transcriptomic and proteomic alterations in ELP components implicate broad ELP dysfunction as a causal contributor to PD and suggest that additional, uncharacterized ELP genes may cooperate in polygenic disease mechanisms. A promising but underexplored therapeutic concept is that targeted manipulation of specific ELP genes may confer protection against αSyn-induced pathology. Distinguishing pathogenic from compensatory ELP alterations could therefore reveal strategies to enhance endogenous protective responses or counteract deleterious ones. Using an integrative multi-omic network approach, we identified high-weight subnetworks of dysregulated ELP genes that converge on known PD risk factors and potential therapeutic nodes. Experimental validation in a Drosophila model demonstrates subnetworks playing a causal role in disease progression. Notably, Endosomal Sorting Complex Required for Transport (ESCRT) and phosphatidylinositol cycle subnetworks contain multiple genes whose perturbation either worsens or mitigates PD-relevant phenotypes. Among these, manipulation of STAM1/2, INPP4A/B, and TMEM55A/B ameliorates behavioral deficits, reduces neurodegeneration, and protects dopaminergic neurons. Collectively, these findings provide new mechanistic insight into the contribution of ELP dysfunction to PD, nominate previously unrecognized therapeutic targets and risk factors, and illustrate a generalizable strategy for identifying interventions capable of reprogramming maladaptive ELP responses in neurodegeneration.

Parkinson’s disease (PD) starts decades before symptoms appear, usually in the later decades of life, when age-related changes are occurring. To identify molecular changes early in the disease course and distinguish PD pathologies from aging, we generated Drosophila expressing alpha-synuclein (αSyn) in neurons and performed longitudinal bulk transcriptomics and proteomics on brains at six time points across the lifespan and compared the data to healthy control flies as well as human post-mortem brain datasets. We found that translational and energy metabolism pathways were downregulated in αSyn flies at the earliest timepoints; comparison with the aged control flies suggests that elevated αSyn accelerates changes associated with normal aging. Unexpectedly, single-cell analysis at a mid-disease stage revealed that neurons upregulate protein synthesis and nonsense-mediated decay, while glia drive their overall downregulation. Longitudinal multi-omics approaches in animal models can thus help elucidate the molecular cascades underlying neurodegeneration vs. aging and co-pathologies.

Neurodegenerative disease is marked not just by loss of proteins or cells, but by dynamic rewiring of macromolecular interaction networks that precede and drive pathology. Here, we present the first temporally resolved, systems-scale map of multi-protein complex remodeling in a tauopathy model, integrating cofractionation mass spectrometry, quantitative phosphoproteomics, and machine learning to decode phosphorylation-dependent shifts in protein interactomes across disease progression. This interactomic atlas identifies functionally validated assemblies, including MAPT::Dpysl2 and Cyfip1::actin complexes that modulate early disease phenotypes in vivo. By revealing how phosphorylation tunes macromolecular complex architecture and function, this work reframes tauopathy as a disease of dynamic network instability, and establishes a generalizable framework for early detection and mechanistic dissection of neurodegeneration.

Huntington’s disease (HD) is a debilitating neurodegenerative disorder affecting an individual’s cognitive and motor abilities. HD is caused by a mutation in the huntingtin gene producing a toxic polyglutamine-expanded protein (mHTT) and leading to degeneration in the striatum and cortex. Yet, the molecular signatures that underlie tissue-specific vulnerabilities remain unclear. Here, we investigate this aspect by leveraging multi-epitope protein interaction assays, subcellular fractionation, thermal proteome profiling, and genetic modifier assays. The use of human cell, mouse, and fly models afforded capture of distinct subcellular pools of epitope-enriched and tissue-dependent interactions linked to dysregulated cellular pathways and disease relevance. We established an HTT association with nearly all subunits of the transcriptional regulatory Mediator complex (20/26), with preferential enrichment of MED15 in the tail domain. Using HD and KO models, we find HTT modulates the subcellular localization and assembly of the Mediator. We demonstrated striatal enriched and functional interactions with regulators of calcium homeostasis and chromatin remodeling, whose disease relevance was supported by HD fly genetic modifiers assays. Altogether, we offer insights into tissue- and localization-dependent (m)HTT functions and pathobiology.

Genome-wide association studies (GWASs) in Alzheimer disease (AD) have uncovered over 70 loci significantly associated with AD risk, but identifying the true causal gene(s) at these loci requires systematic functional validation that is rarely performed due to limitations of time and cost. Here, we integrate transcriptome-wide association study (TWAS) with colocalization analysis, fine-mapping, and additional annotation of AD GWAS variants to identify 123 genes at known and suggestive AD risk loci. A comparison with human AD brain transcriptome data confirmed that many of these candidate genes are dysregulated in human AD and correlate with neuropathology. We then tested all available orthologs in two well-established Drosophila AD models that express either wild-type tau or secreted β-amyloid (β42). Experimental perturbation of the 60 available candidates pinpointed 46 that modulated neuronal dysfunction in one or both fly models. The effects of 18 of these genes were concordant with the TWAS prediction, such that the direction of misexpression predicted to increase AD risk in humans exacerbated behavioral impairments in the AD fly models. Reversing the aberrant down- or upregulation of 11 of these genes (MTCH2, ELL, TAP2, HDC, DMWD, MYCL, SLC4A9, ABCA7, CSTF1, PTK2B, and CD2AP) proved neuroprotective in vivo. We further studied MTCH2 and found that it regulates steady-state tau protein levels in the Drosophila brain and reduces tau accumulation in human neural progenitor cells. This systematic, integrative approach effectively prioritizes genes at GWAS loci and reveals promising AD-relevant candidates for further investigation as risk factors or targets for therapeutic intervention.

Most Alzheimer disease (AD) susceptibility genes have poorly understood roles in the central nervous system (CNS). To address this gap, we systematically characterized 100 conserved candidate AD risk genes using a cross-species strategy in the fruit fly, Drosophila melanogaster. Genes were prioritized based primarily on human functional genomic evidence. We generated custom loss-of-function alleles for each of the conserved fly orthologs. Most of the genes are expressed in the adult brain, including 24 neuron- and 13 glia-specific expression patterns. Overall, we identify 50 candidate AD risk gene homologs with requirements for CNS structure or function, including 18 whose loss of function causes neurodegeneration (e.g., Snx6/SNX32 and ClC-a/CLCN1), 35 required for neurophysiology (e.g., Arr1/ARRB2 and stai/STMN4), and eight with diminished CNS resilience following a thermal or mechanical stress (e.g., cindr/CD2AP and Amph/BIN1). In a parallel screen, we found 28 AD risk gene homologs (e.g., Ets98B/SPI1 and Yod1/YOD1) that modify the neurotoxicity of either amyloid-β peptide or tau protein, which aggregate to form AD pathology. To translate our findings back to human AD, we used oligogenic risk scores based on gene clusters with shared nervous system phenotypes in flies, pinpointing functional pathways that differentially drive AD risk. Our results-available online via the Alzheimer's Locus Integrative Cross-species Explorer portal-reveal nervous system requirements for dozens of AD risk genes and may enable dissection of causal heterogeneity in AD.

Alzheimer’s disease (AD) has a complex etiology where insults in multiple pathways conspire to disrupt neuronal function, yet molecular changes underlying AD remain poorly understood. Previously, we performed mass-spectrometry on post-mortem human brain tissue to identify >40 protein co-expression modules correlated to AD pathological and clinical traits. Module 42 has the strongest correlation to AD pathology and consists of 32 proteins including SMOC1, a predicted driver of network behavior and potential biomarker for AD. SMOC1 is a matrisomal protein with conserved roles in modulating TGF-Beta and wnt signaling during development, yet remains unstudied in the brain. We evaluate M42 using a high-throughput robotic screening platform and video assisted software, enabling quantitative assessments of neurological function to identify proteins that modify Aβ- or tau-induced neurodegeneration. We then focus on dSMOC1 using Drosophila genetics and cell biological approaches to determine its role in the brain. Finally, we use Mass Spectrometry to identify protein changes in the brains of dSMOC1 -/- flies. Our screening assay identified 20 genes from M42 that modify tau toxicity and 5 for Aβ, including dSMOC1 and components of Wnt and TGF-β signaling pathways. We find dSMOC1 -/- null flies suffer severely decreased survival and climbing defects upon aging. In the brain, dSMOC1 expression occurs primarily in glial cells while protein localizes around neuronal cell bodies, consistent with its role as a matrisomal protein. We show alteration of glypican levels in dSMOC1 -/- brains. Glypicans modulate Wnt and TGF-β signaling further supporting a role connecting M42 in AD biology. Finally, we used mass spectrometry to determine protein changes in brains of dSMOC1 -/- flies and found perturbations in ECM/receptor interactions, proteostasis, KREBs/TCA cycle, and oxidative phosphorylation. Additional data suggests an age dependent shift from oxidative phosphorylation to glycolysis may compensate for reduced ATP levels in dSMOC1 -/- flies. The M42 protein module contains multiple proteins with links to AD. Multiple M42 proteins interact with specific AD triggers including SMOC1, wnt and TGF-β signaling components. The genetics, proteomics, and cell biological data combine to support a mechanistic hypothesis where changes in SMOC1 levels disrupt critical signaling pathways leading to disruptions in metabolism affecting neuronal function.

Alzheimer’s Disease (AD) incidence is almost double in female than male, suggesting sex-specific AD risk genes remain unknown. We designed a statistical physics approach that exploits freely available but massive evolutionary and phylogenetic coupling data on sequence variation and speciation. These couplings lead to quantifiable values for the selection pressure exerted on the genes within a population. We may then compare a gene’s influence in sequenced cases vs controls cohorts and test the hypothesis that significant deviations identify genes linked to disease risk. In 4768 AD cases and 4689 healthy controls (HC), we discovered 122 genes under greater selection pressure (q < 0.01). These genes overlapped (p = 3.10 -5 ) and interacted (z = 7.16) with AD GWAS genes. They also interacted mutually (n = 57, p = 0.0019) and with AD-related processes (p = 1.0 -16 ). More than 50% of the genes exhibited dysregulation in AD brains in snRNAseq analysis, suggesting participation in pathogenic or protective processes in AD. Furthermore, expression of these genes correlated with increased or decreased deposition of plaques and tangles in patient brains. Moreover, the candidates are enriched in modifiers of neurodegeneration in Drosophila : knockdown or overexpression of 64 genes ameliorated or worsened age-dependent neuronal dysfunction (p<0.05). Robustness to down-sampling allowed to analyze smaller, sex-separated cohorts. We identified 82 genes in males and 69 genes in females (15 genes overlapped, p < 10 -53 ), indicating shared as well as sex-specific AD mechanisms. The male and the female genes overlapped (p = 6.5 -6 and 1.5 -4 ) and interacted (z = 5.63 and 6.18) with the AD genes. Remarkably, using these gene sets as features for predicting AD risk in separate training and testing cohorts successfully differentiated between AD cases and controls with very high accuracy, even when blinded to APOE genotype. Notably, we predicted the risk with AUCs of 0.83 with APOE, 0.83, and 0.82 in combined, males, and females, respectively. A new statistical physics approach discovered male and female AD genes, predicting AD risk with very high accuracy. These results identify further genetic differences leading to AD in males and females, and show the power of quantitative phylogenetics to probe complex human diseases.

Genomic and transcriptomic analyses have identified molecular pathways dysregulated in Alzheimer's disease (AD). However, their roles in disease remain largely unknown due to limited in vivo validation. YAP1, a downstream effector of the Hippo pathway, has been shown to be dysregulated in AD and sequestered into amyloid aggregates. Additionally, studies have shown that suppressing Hippo kinase activity improves outcomes in AD animal models (PMIDs: 31980612, 35525373, 38760516). This study explores the interaction between the Hippo pathway and Tau, examining how its dysregulation contributes to AD pathogenesis and providing new mechanistic insights into the therapeutic potential of targeting the Hippo pathway. We analyzed brain transcriptomes from Alzheimer's disease (AD) patients (bulk and single-nucleus) and AD mouse models. Additionally, whole-exome sequencing data from ADSP revealed differential mutational burdens in Hippo pathway genes between AD cases and controls. To validate and characterize the interaction between the Hippo pathway and Tau, we employed behavioral, biochemical, and histopathological assays in vivo and in human NPCs. Genomic analyses of AD suggest an increased mutational burden in Hippo pathway genes compared to controls, while transcriptomic data indicate dysregulation consistent with pathway activation. These in silico findings were validated in vivo. We demonstrate that Hippo pathway modulation can suppress Tau-mediated neuronal dysfunction in Drosophila. Additionally, knockdown of several Hippo pathway genes reduces Tau protein levels in both Tauopathy fly and human NPC models. Furthermore, Tau and YAP1 co-immunoprecipitate in human NPCs and brains from aged P301S mice. Our findings reveal aberrant Hippo pathway activation and increased mutations in AD. Modulating pathway components reduces Tau toxicity and lowers Tau levels, highlighting the Hippo pathway as a potential diagnostic and therapeutic target.

In Alzheimer’s disease (AD), changes in the brain transcriptome are hypothesized to mediate the impact of neuropathology on cognition. Gene expression profiling from postmortem brain tissue is a promising approach to identify causal pathways; however, there are challenges to definitively resolve the upstream pathologic triggers along with the downstream consequences for AD clinical manifestations. We have functionally dissected 30 AD-associated gene coexpression modules using a cross-species strategy in Drosophila melanogaster models. First, integrating longitudinal RNA-sequencing and fly behavioral phenotyping, we interrogated unique and shared transcriptional responses to amyloid beta (Aβ) plaques, tau neurofibrillary tangles, and/or aging, along with potential links to progressive neuronal dysfunction. In order to confirm causal modules and pinpoint AD network drivers, we next performed systematic in vivo genetic manipulations of 357 conserved, prioritized targets to identify modifiers of Aβ- and/or tau-induced neurodegeneration. We subsequently partitioned candidate causal subnetworks, which were further validated based on human or Drosophila genetic evidence. Our results highlight hundreds of conserved, differentially expressed genes mapping to AD regulatory networks. Our systematic screening identified 144 tau/Aβ modifiers. We discovered an up-regulated, causal network that is significantly enriched for both AD risk variants and markers of immunity / inflammation, and which promotes Aβ and tau-mediated neurodegeneration based on fly genetic manipulations in neurons. By contrast, a promising synaptic regulatory network is strongly downregulated in human AD and is enriched for loss-of-function suppressors of Aβ/tau, consistent with a potential compensatory response to glutamatergic excitotoxic brain injury. our cross-species, systems genetic approach establishes a putative causal chain linking AD pathology, large-scale gene expression perturbations, and ultimately, neurodegeneration.

Loss-of-function mutations in methyl-CpG binding protein 2 (MECP2) cause Rett syndrome. While we know that MeCP2 binds to methylated cytosines on DNA, the full breadth of the molecular mechanisms by which MeCP2 regulates gene expression remains incompletely understood. Here, using a genetic modifier screen, we identify the super elongation complex, a P-TEFb-containing elongation factor that releases promoter-proximally paused RNA polymerase II, as a genetic interactor of MECP2. MeCP2 physically interacts with SEC subunits and directly binds AFF4, the scaffold of the SEC, via the transcriptional repression domain. Furthermore, MeCP2 facilitates the binding of AFF4 on a subset of genes in the mouse brain regulating synaptic plasticity and concordantly promotes the binding of RNA polymerase II on these genes. Last, while haploinsufficiency of Aff4 does not exhibit any behavioral deficits in mice, it exacerbates the impaired contextual learning behavior of Mecp2 hypomorphic mice. We propose a previously unknown mechanism by which MePC2 regulates gene expression underlying synaptic plasticity.

Alzheimer's disease (AD) has a complex etiology where insults in multiple pathways collude to disrupt neuronal function, yet the molecular changes underlying AD remain poorly understood. To identify changes associated with AD, we previously performed mass-spectrometry on post-mortem brain tissue and identified protein co-expression networks correlated to AD pathological and clinical traits. The network most strongly correlated with AD pathology is enriched in components of the matrisome and includes multiple signaling pathways, Aß, APOE, and SMOC1, a predicted driver of network behavior. SMOC1 is a matrisomal protein with conserved roles in modulating signaling during development, yet its role in the adult brain remains unstudied. We evaluate the SMOC1 protein network using the powerful genetics of Drosophila melanogaster to determine its role in the brain and uncover links to specific triggers of AD: Amyloid-Beta (Aβ) and tau. We use a high-throughput robotic screening platform and video assisted software enabling quantitative assessments of neurological function to identify proteins modifying Aβ- or tau-induced neurodegeneration. We use Mass-Spectrometry to identify protein changes in the brains of flies with loss-of-function mutations in dSMOC1 and genetics, cell biology, and immunofluorescence to characterize dSMOC1 function. We identified 25 genes from the SMOC1 network with robust evidence of interactions with either tau or Aβ toxicity in fly AD models. Consistent with its central, interconnected position within the network, dSMOC1 shows genetic interactions with at least 8 other network genes. dSMOC1 is expressed in the brain by many glia and some neurons, however, dSMOC1 protein is mainly localized around neuronal cell bodies. dSMOC1 -/- mutant flies have severe locomotor defects, reduced survival, and show cell-type specific changes in glypican expression, potentially linking the network to Wnt and TGF-β signaling. Finally, proteomics from dSMOC1 -/- fly heads show perturbations in ECM/Receptor interactions, metabolism, signaling, and proteostasis The SMOC1 protein network contains multiple proteins with links to AD, and dSMOC1 is likely a key driver of network function. Together, the genetics and proteomics data show that dSMOC1 is an important regulator of extracellular matrix function in the brain and suggest a mechanistic hypothesis where dSMOC1 fine-tunes multiple signaling modalities to regulate cellular homeostasis.

X-linked adrenoleukodystrophy (X-ALD) is a progressive neurodegenerative disorder caused by a loss-of-function (LOF) mutation in the ATP-binding cassette subfamily D member 1 (ABCD1) gene, leading to the accumulation of very long-chain fatty acids (VLCFAs). This disorder exhibits striking heterogeneity; some male patients develop an early childhood neuroinflammatory demyelination disorder, while other patients, including adult males and most affected female carriers, experience a chronic progressive myelopathy. Adrenocortical failure is observed in almost all male patients, with age of onset varying sometimes being the first diagnostic finding. The gene underlying this spectrum of disease encodes an ATP-binding cassette (ABC) transporter that localizes to peroxisomes and facilitates VLCFA transport. X-ALD is considered a single peroxisomal component defect and does not play a direct role in peroxisome assembly. Drosophila models of other peroxisomal genes have provided mechanistic insight into some of the neurodegenerative mechanisms with reduced lifespan, retinal degeneration, and VLCFA accumulation. Here, we perform a genetic analysis of the fly ABCD1 ortholog Abcd1 (CG2316). Knockdown or deficiency of Abcd1 leads to VLCFA accumulation, salivary gland defects, locomotor impairment and retinal lipid abnormalities. Interestingly, there is also evidence of reduced peroxisomal numbers. Flies overexpressing the human cDNA for ABCD1 display a wing crumpling phenotype characteristic of the pex2 loss-of-function. Surprisingly, overexpression of human ABCD1 appears to inhibit or overwhelm peroxisomal biogenesis to levels similar to null mutations in fly pex2, pex16 and pex3. Drosophila Abcd1 is therefore implicated in peroxisomal number, and overexpression of the human ABCD1 gene acts a potent inhibitor of peroxisomal biogenesis in flies.

Tauopathies are neurodegenerative diseases that involve the pathological accumulation of tau proteins; in this family are Alzheimer disease, corticobasal degeneration, and chronic traumatic encephalopathy, among others. Hypothesizing that reducing this accumulation could mitigate pathogenesis, we performed a cross-species genetic screen targeting 6,600 potentially druggable genes in human cells and Drosophila. We found and validated 83 hits in cells and further validated 11 hits in the mouse brain. Three of these hits (USP7, RNF130, and RNF149) converge on the C terminus of Hsc70-interacting protein (CHIP) to regulate tau levels, highlighting the role of CHIP in maintaining tau proteostasis in the brain. Knockdown of each of these three genes in adult tauopathy mice reduced tau levels and rescued the disease phenotypes. This study thus identifies several points of intervention to reduce tau levels and demonstrates that reduction of tau levels via regulation of this pathway is a viable therapeutic strategy for Alzheimer disease and other tauopathies.