Protein Aggregates In Neurons Research Articles

Role of TFEB in Huntington's Disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expansion of the CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. This expansion leads to a polyglutamine (polyQ) tract at the N-terminal end of HTT, which reduces the solubility of the protein and promotes its accumulation. Inefficient clearance of mutant HTT (mHTT) by the proteasome or autophagy-lysosomal system leads to accumulation of oligomers and toxic protein aggregates in neurons, resulting in impaired proteolytic systems, transcriptional dysregulation, impaired axonal transport, mitochondrial dysfunction and cellular energy imbalance. Growing evidence suggests that the accumulation of mHTT aggregates and autophagic and/or lysosomal dysfunction are the major pathogenic mechanisms underlying HD. In this context, enhancing autophagy may be an effective therapeutic strategy to remove protein aggregates and improve cell function. Transcription factor EB (TFEB), a master transcriptional regulator of autophagy, controls the expression of genes critical for autophagosome formation, lysosomal biogenesis, lysosomal function and autophagic flux. Consequently, the induction of TFEB activity to promote intracellular clearance may be a therapeutic strategy for HD. However, while some studies have shown that overexpression of TFEB facilitates the clearance of mHTT aggregates and ameliorates the disease phenotype, others indicate such overexpression may lead to mHTT co-aggregation and worsen disease progression. Further studies are necessary to confirm whether TFEB modulation could be an effective therapeutic strategy against mHTT-mediated toxicity in different disease models.

Interplay between autophagy and CncC regulates dendrite pruning in Drosophila

Autophagy is essential for the turnover of damaged organelles and long-lived proteins. It is responsible for many biological processes such as maintaining brain functions and aging. Impaired autophagy is often linked to neurodevelopmental and neurodegenerative diseases in humans. However, the role of autophagy in neuronal pruning during development remains poorly understood. Here, we report that autophagy regulates dendrite-specific pruning of ddaC sensory neurons in parallel to local caspase activation. Impaired autophagy causes the formation of ubiquitinated protein aggregates in ddaC neurons, dependent on the autophagic receptor Ref(2)P. Furthermore, the metabolic regulator AMP-activated protein kinase and the insulin-target of rapamycin pathway act upstream to regulate autophagy during dendrite pruning. Importantly, autophagy is required to activate the transcription factor CncC (Cap "n" collar isoform C), thereby promoting dendrite pruning. Conversely, CncC also indirectly affects autophagic activity via proteasomal degradation, as impaired CncC results in the inhibition of autophagy through sequestration of Atg8a into ubiquitinated protein aggregates. Thus, this study demonstrates the important role of autophagy in activating CncC prior to dendrite pruning, and further reveals an interplay between autophagy and CncC in neuronal pruning.

Comparative assessment of α‐synuclein seeding activities in the cerebrospinal fluid of MCI patients phenoconverting to DLB

AbstractBackgroundDementia with Lewy bodies (DLB), the second most prevalent form of degenerative dementia, is characterized by pathological α‐synuclein (αSyn) protein aggregation in neurons. Pathological αSyn shows a protein‐seeding phenomenon that may result in aggregation years before clinical symptoms. Studies using Real‐time quaking‐induced conversion (RT‐QuIC) assay show αSyn seeding from peripheral tissue including skin and cerebrospinal Fluid (CSF). Identifying early biomarkers for DLB is essential for accurate diagnosis, and developing effective treatments to slow progression. Herein, we investigate αSyn seeding activities in CSF from patients with mild cognitive impairment with Lewy bodies (MCI‐LB) phenoconverting to DLB.MethodCSF samples were obtained from 3 MCI‐LB and 2 DLB patients at baseline and two‐year follow‐up appointments. CSF samples were tested for their potential to seed α‐synuclein aggregation using an RT‐QuIC assay. CSF samples were tested by seeding 2 μl of CSF in 98 ul of RT‐QuIC reaction mixture with human recombinant αSyn protein, analyzed on a FLUOstar Omega plate reader. Results were recorded every 30 minutes over a period of 45 hours analyzed based on the reaction kinetics to determine the seeding ability of the α‐synuclein in the CSF samples.ResultWe observed seed amplification at first visit for both DLB patients and one MCI‐LB patient. The absolute quantification of aggregation increased at second visit (2 years apart) for one DLB patient and one MCI‐LB. The other two MCI‐LB patients showed no amplification at baseline visit but showed signal at two‐year visit, by which time all three had phenoconverted to DLB. Interestingly the second DLB patient showed a decline at two‐year follow‐up. The medical and neuroimaging records of that patient indicate that the patient’s cognitive decline began as early‐onset disease (first symptoms at age 50 years).ConclusionWe demonstrate that measures of seed aggregation in CSF with RT‐QuIC are informative in MCI‐LB and DLB, and may also reflect changes in disease progression and dynamics.

NGLY1 mutations cause protein aggregation in human neurons

Biallelic mutations in the gene that encodes the enzyme N-glycanase 1 (NGLY1) cause a rare disease with multi-symptomatic features including developmental delay, intellectual disability, neuropathy, and seizures. NGLY1's activity in human neural cells is currently not well understood. To understand how NGLY1 gene loss leads to the specific phenotypes of NGLY1 deficiency, we employed direct conversion of NGLY1 patient-derived induced pluripotent stem cells (iPSCs) to functional cortical neurons. Transcriptomic, proteomic, and functional studies of iPSC-derived neurons lacking NGLY1 function revealed several major cellular processes that were altered, including protein aggregate-clearing functionality, mitochondrial homeostasis, and synaptic dysfunctions. These phenotypes were rescued by introduction of a functional NGLY1 gene and were observed in iPSC-derived mature neurons but not astrocytes. Finally, laser capture microscopy followed by mass spectrometry provided detailed characterization of the composition of protein aggregates specific to NGLY1-deficient neurons. Future studies will harness this knowledge for therapeutic development.

Neuroinflammation-Modulating Agent SB1617 Enhances LC3-Associated Phagocytosis to Mitigate Tau Pathology.

Tau protein aggregation and propagation in neurons and surrounding microglia are well-known risk factors for neurodegenerative diseases. Therefore, emerging therapeutic strategies that target neuroinflammatory activity in microglia have the potential to prevent tauopathy. Here, we explored the microglia-mediated neuroprotective function of SB1617 against tau aggregation. Our study revealed that SB1617-inactivated pathogenic M1-like microglia, reduced the secretion of pro-inflammatory cytokines via translational regulation, and induced microglial polarization toward the M2 phenotype and phagocytic function. Furthermore, we observed that extracellular pathogenic tau aggregates were eliminated via LC3-associated phagocytosis. The in vivo efficacy of SB1617 was confirmed in mice with traumatic brain injury in which SB1617 exerted neuroprotective effects by reducing pathogenic tau levels through microglia-mediated anti-inflammatory activity. Our results indicated that SB1617-mediated microglial surveillance with LC3-associated phagocytosis is a critical molecular mechanism in the regulation of tau proteostasis. This study provides new insights into tauopathies and directions for developing novel therapies for neurodegenerative diseases.

Clinical application of MAO-B PET using 18F-THK5351 in neurological disorders.

Monoamine oxidase B (MAO-B) is an enzyme localized to the outer mitochondrial membrane and highly concentrated in astrocytes. Temporal changes in regional MAO-B levels can be used as an index of astrocytic proliferation, known as activated astrocytes or astrogliosis. MAO-B is a marker to evaluate the degree of astrogliosis. Therefore, MAO-B positron emission tomography (PET) is a powerful imaging technique for visualizing and quantifying ongoing astrogliosis through the estimate of regional MAO-B levels. Each neurodegenerative disorder generally has a characteristic distribution pattern of astrogliosis secondary to neuronal loss and pathological protein aggregation. Therefore, by imaging astrogliosis, MAO-B PET can be used as a neurodegeneration marker for identifying degenerative lesions. Any inflammation in the brain usually accompanies astrogliosis starting from an acute phase to a chronic phase. Therefore, by imaging astrogliosis, MAO-B PET can be used as a neuroinflammation marker for identifying inflammatory lesions. MAO-B levels are high in gliomas originating from astrocytes but low in lymphoid tumors. Therefore, MAO-B PET can be used as a brain tumor marker for identifying astrocytic gliomas by imaging MAO-B levels and distinguishing between astrocytic and lymphoid tumors. This review summarizes the clinical application of MAO-B PET using 18F-THK5351 as markers for neurodegeneration, neuroinflammation, and brain tumors in neurological disorders. Because we assume that MAO-B PET is clinically applied to an individual patient, we focus on visual inspection of MAO-B images at the individual patient level. Geriatr Gerontol Int 2024; 24: 31-43.

Navigating the Gene Co-Expression Network and Drug Repurposing Opportunities for Brain Disorders Associated with Neurocognitive Impairment.

Neurocognitive impairment refers to a spectrum of disorders characterized by a decline in cognitive functions such as memory, attention, and problem-solving, which are often linked to structural or functional abnormalities in the brain. While its exact etiology remains elusive, genetic factors play a pivotal role in disease onset and progression. This study aimed to identify highly correlated gene clusters (modules) and key hub genes shared across neurocognition-impairing diseases, including Alzheimer's disease (AD), Parkinson's disease with dementia (PDD), HIV-associated neurocognitive disorders (HAND), and glioma. Herein, the microarray datasets AD (GSE5281), HAND (GSE35864), glioma (GSE15824), and PD (GSE7621) were used to perform Weighted Gene Co-expression Network Analysis (WGCNA) to identify highly preserved modules across the studied brain diseases. Through gene set enrichment analysis, the shared modules were found to point towards processes including neuronal transcriptional dysregulation, neuroinflammation, protein aggregation, and mitochondrial dysfunction, hallmarks of many neurocognitive disorders. These modules were used in constructing protein-protein interaction networks to identify hub genes shared across the diseases of interest. These hub genes were found to play pivotal roles in processes including protein homeostasis, cell cycle regulation, energy metabolism, and signaling, all associated with brain and CNS diseases, and were explored for their drug repurposing experiments. Drug repurposing based on gene signatures highlighted drugs including Dorzolamide and Oxybuprocaine, which were found to modulate the expression of the hub genes in play and may have therapeutic implications in neurocognitive disorders. While both drugs have traditionally been used for other medical purposes, our study underscores the potential of a combined WGCNA and drug repurposing strategy for searching for new avenues in the simultaneous treatment of different diseases that have similarities in gene co-expression networks.

Glial-derived mitochondrial signals affect neuronal proteostasis and aging.

The nervous system plays a critical role in maintaining whole-organism homeostasis; neurons experiencing mitochondrial stress can coordinate the induction of protective cellular pathways, such as the mitochondrial unfolded protein response (UPRMT), between tissues. However, these studies largely ignored nonneuronal cells of the nervous system. Here, we found that UPRMT activation in four astrocyte-like glial cells in the nematode, Caenorhabditis elegans, can promote protein homeostasis by alleviating protein aggregation in neurons. Unexpectedly, we find that glial cells use small clear vesicles (SCVs) to signal to neurons, which then relay the signal to the periphery using dense-core vesicles (DCVs). This work underlines the importance of glia in establishing and regulating protein homeostasis within the nervous system, which can then affect neuron-mediated effects in organismal homeostasis and longevity.

The identification of high-performing antibodies for Charged multivesicular body protein 2b for use in Western Blot, immunoprecipitation and immunofluorescence.

Charged multivesicular body protein 2B is a subunit of the endosomal sorting complex required for transport III (ESRCT-III), a complex implicated in the lysosomal degradation pathway and formation of multivesicular bodies. Mutations to the CHMP2B gene can result in abnormal protein aggregates in neurons and is therefore predicted to be associated in neurodegenerative diseases, including across the ALS-FTD spectrum.Through our standardized experimental protocol which compares read-outs in knockout cell lines and isogenic parental controls, this study aims to enhance the reproducibility of research on this target by characterizing eight commercial antibodies against charged multivesicular body protein 2b using Western Blot, immunoprecipitation, and immunofluorescence. We identified many high-performing antibodies and encourage readers to use this report as a guide to select the most appropriate antibody for their specific needs.

LONRF2 is a gatekeeper against protein aggregation in aging neurons.

LONRF2 is a gatekeeper against protein aggregation in aging neurons.

Toxicity of copper and zinc alone and in combination in Caenorhabditis elegans model of Huntington's disease and protective effects of rutin

Copper (Cu) and Zinc (Zn) are required in small concentrations for metabolic functions, but are also toxic. There is a great concern about soil pollution by heavy metals, which may exposure the population to these toxicants, either by inhalation of dust or exposure to toxicants through ingestion of food derived from contaminated soils. In addition, the toxicity of metals in combination is questionable, as soil quality guidelines only assess them separately. It is well known that metal accumulation is often found in the pathologically affected regions of many neurodegenerative diseases, including Huntington's disease (HD). HD is caused by an autosomal dominantly inherited CAG trinucleotide repeat expansion in the huntingtin (HTT) gene. This results in the formation of a mutant huntingtin (mHTT) protein with an abnormally long polyglutamine (polyQ) repeat. The pathology of HD results in loss of neuronal cells, motor changes, and dementia. Rutin is a flavonoid found in various food sources, and previous studies indicate it has protective effects in HD models and acts as a metal chelator. However, further studies are needed to unravel its effects on metal dyshomeostasis and to discern the underlying mechanisms. In the present study, we investigated the toxic effects of long-term exposure to copper, zinc, and their mixture, and the relationship with the progression of neurotoxicity and neurodegeneration in a C. elegans-based HD model. Furthermore, we investigated the effects of rutin post metal exposure. Overall, we demonstrate that chronic exposure to the metals and their mixture altered body parameters, locomotion, and developmental delay, in addition to increasing polyQ protein aggregates in muscles and neurons causing neurodegeneration. We also propose that rutin has protective effects acting through mechanisms involving antioxidant and chelating properties. Altogether, our data provides new indications about the higher toxicity of metals in combination, the chelating potential of rutin in the C. elegans model of HD and possible strategies for future treatments of neurodegenerative diseases caused by the aggregation of proteins related to metals.

Unconventional Source of Neurotoxic Protein Aggregation from Organelle Off-Target Bax∆2 in Alzheimer’s Disease

Protein aggregates are a hallmark of Alzheimer’s disease (AD). Extensive studies have focused on β-amyloid plaques and Tau tangles. Here, we illustrate a novel source of protein aggregates in AD neurons from organelle off-target proteins. Bax is a mitochondrial pore-forming pro-death protein. What happens to Bax if it fails to target mitochondria? We previously showed that a mitochondrial target-deficient alternatively spliced variant, Bax∆2, formed large cytosolic protein aggregates and triggered caspase 8-mediated cell death. Bax∆2 protein levels were low in most normal organs and the proteins were quickly degraded in cancer. Here, we found that 85% of AD patients had Bax∆2 required alternative splicing. Increased Bax∆2 proteins were mostly accumulated in neurons of AD-susceptible brain regions. Intracellularly, Bax∆2 aggregates distributed independently of Tau tangles. Interestingly, Bax∆2 aggregates triggered the formation of stress granules (SGs), a large protein-RNA complex involved in AD pathogenesis. Although the functional domains required for aggregation and cell death are the same as in cancer cells, Bax∆2 relied on SGs, not caspase 8, for neuronal cell death. These results imply that the aggregation of organelle off-target proteins, such as Bax∆2, broadens the scope of traditional AD pathogenic proteins that contribute to the neuronal stress responses and AD pathogenesis.

The polyphenol EGCG directly targets intracellular amyloid-β aggregates and promotes their lysosomal degradation.

The accumulation of amyloidogenic protein aggregates in neurons is a pathogenic hallmark of a large number of neurodegenerative diseases including Alzheimer's disease (AD). Small molecules targeting such structures and promoting their degradation may have therapeutic potential for the treatment of AD. Here, we searched for natural chemical compounds that decrease the abundance of stable, proteotoxic β-sheet-rich amyloid-β (Aβ) aggregates in cells. We found that the polyphenol (-)-epigallocatechin gallate (EGCG) functions as a potent chemical aggregate degrader in SH-EP cells. We further demonstrate that a novel, fluorescently labeled EGCG derivative (EGC-dihydroxybenzoate (DHB)-Rhodamine) also shows cellular activity. It directly targets intracellular Aβ42 aggregates and competes with EGCG for Aβ42 aggregate binding in vitro. Mechanistic investigations indicated a lysosomal accumulation of Aβ42 aggregates in SH-EP cells and showed that lysosomal cathepsin activity is critical for efficient EGCG-mediated aggregate clearance. In fact, EGCG treatment leads to an increased abundance of active cathepsin B isoforms and increased enzymatic activity in our SH-EP cell model. Our findings suggest that intracellular Aβ42 aggregates are cleared through the endo-lysosomal system. We show that EGCG directly targets intracellular Aβ42 aggregates and facilitates their lysosomal degradation. Small molecules, which bind to protein aggregates and increase their lysosomal degradation could have therapeutic potential for the treatment of amyloid diseases.

Oolong tea polyphenols affect the inflammatory response to improve cognitive function by regulating gut microbiota

Oolong tea polyphenols (OTP) has received increasing attention for their ability to reduce cognitive dysfunction by modulating the gut microbiota and related metabolites. In our study, the circadian rhythm disorder (CRD) mice showed gut microbial disruption and cognitive impairments. OTP treatment restored the gut microbiota disruption including up-regulated the relative abundance of Akkermansia and Muribaculum, and down-regulated Desulfovibrio. Moreover, OTP reduced inflammation response, decreased lipopolysaccharide (LPS) levels, and strengthened tight junction proteins (TJPs) to ameliorate intestinal barrier dysfunction. These changes inhibited the elevated levels of pro-inflammatory factors, therefore, attenuated neuronal damage and Aβ protein aggregation in the hippocampus. Additionally, OTP supplementation also regulated the levels of metabolites related to cognitive function, some of them closely associated with microbiota. Our findings speculate that OTP potentially modulates cognitive impairment and inflammation caused by circadian disruption by modulating the gut microbiota.

Towards an unbiased shape classification of super-resolution microscopy localizations.

Single molecule localization microscopy (SMLM) captures biological structures at nanoscale spatial resolution and has become an important tool for discovery in cell biology in recent years. However, tools that enable robust quantification of complex biological structures have lagged behind. In this study, we developed a new method to quantitatively describe and classify a wide range of diverse biological structures in SMLM data and have applied it to describe the degradation process of neuronal Tau protein aggregates, an important precursor in neurodegenerative diseases.

Neurodegenerative Diseases due to Neurotoxins passing through the Nose-to-Brain Pathway

Three neurodegenerative disorders- Alzheimer’s dementia (ALZ), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS)- share a common feature in their pathogenesis: evidence of mitochondrial dysfunction and reactive oxygen stress. Their pathologic classifications are based on the findings at autopsy based on patterns of protein aggregates in neurons and glial cells. This pathology supports the concept that neurotoxins are a major factor in the etiology of these disorders. There is value in exploring the similarities in the pathogenesis of ALS, Parkinson Disease and Alzheimer Dementia based on non-genetic etiologies. The nose to olfactory pathway feeds sensory input from the nasal cavity to the olfactory bulb and the entorhinal lobe. Another component of these pathways involves two branches of the trigeminal nerve with sensory input to the pons and midbrain. A key factor is their capacity to bypass the blood-brain barrier (BBB). The protection of the brain by the BBB diminishes with age and can be lost with damage from insults as with viral infections. The olfactory nerve is the only cranial nerve with direct exposure to the ambient environment and has a high rate of turnover of sensory receptors. The nasal cavity is being studied for drug delivery and can be used to deliver medications into the central nervous system (CNS. The nose-to-brain pathway may represent a critical avenue of exposure to oxidative neurotoxins. Neurotoxic mycotoxins are a major risk to humans. Neurotoxins may be amplified by the nose-to-brain pathway. The pathology shows similarities to prion disease. These neurotoxins are highly fat-soluble and tend to accumulate in mitochondria and synaptic vesicles. Neurotoxins in synaptic vesicles can migrate from neuron to neuron. There is evidence of chronic fungal infections in ALS patients that secret neurotoxic and immunotoxic mycotoxins leading to progressive immune suppression. The nose-to-olfactory pathway may amplify neurotoxins levels in the brain. If Parkinson Disease and ALZ are due to systemic poisonings, the source of neurotoxins may be episodic and lead to autoimmune disease.

Site-Specific C-Terminal Fluorescent Labeling of Tau Protein.

Formation of Tau protein aggregates in neurons is a pathological hallmark of several neurodegenerative diseases, including Alzheimer's disease. Fluorescently labeled Tau protein is therefore useful to study the aggregation of these pathological proteins and to identify potential therapeutic targets. Conventionally, cysteine residues are used for labeling Tau proteins; however, the full-length Tau isoform contains two cysteine residues in the microtubule-binding region, which are implicated in Tau aggregation by forming intermolecular disulfide bonds. To prevent the fluorescent label from disturbing the microtubule binding region, we developed a strategy to fluorescently label Tau at its C-terminus while leaving cysteine residues unperturbed. We took advantage of a Sortase A-mediated transpeptidation approach to bind a short peptide (GGGH6-Alexa647) with a His-tag and a covalently attached Alexa 647 fluorophore to the C-terminus of Tau. This reaction relies on the presence of a Sortase recognition motif (LPXTG), which we attached to the C-terminus of recombinantly expressed Tau. We demonstrate that C-terminal modification of Tau protein results in no significant differences between the native and C-terminally labeled Tau monomer with regard to aggregation kinetics, secondary structure, and fibril morphology.

Protein mishandling and impaired lysosomal proteolysis generated through calcium dysregulation in Alzheimer’s disease

Impairments in neural lysosomal- and autophagic-mediated degradation of cellular debris contribute to neuritic dystrophy and synaptic loss. While these are well-characterized features of neurodegenerative disorders such as Alzheimer's disease (AD), the upstream cellular processes driving deficits in pathogenic protein mishandling are less understood. Using a series of fluorescent biosensors and optical imaging in model cells, AD mouse models and human neurons derived from AD patients, we reveal a previously undescribed cellular signaling cascade underlying protein mishandling mediated by intracellular calcium dysregulation, an early component of AD pathogenesis. Increased Ca2+ release via the endoplasmic reticulum (ER)-resident ryanodine receptor (RyR) is associated with reduced expression of the lysosome proton pump vacuolar-ATPase (vATPase) subunits (V1B2 and V0a1), resulting in lysosome deacidification and disrupted proteolytic activity in AD mouse models and human-induced neurons (HiN). As a result of impaired lysosome digestive capacity, mature autophagosomes with hyperphosphorylated tau accumulated in AD murine neurons and AD HiN, exacerbating proteinopathy. Normalizing AD-associated aberrant RyR-Ca2+ signaling with the negative allosteric modulator, dantrolene (Ryanodex), restored vATPase levels, lysosomal acidification and proteolytic activity, and autophagic clearance of intracellular protein aggregates in AD neurons. These results highlight that prior to overt AD histopathology or cognitive deficits, aberrant upstream Ca2+ signaling disrupts lysosomal acidification and contributes to pathological accumulation of intracellular protein aggregates. Importantly, this is demonstrated in animal models of AD, and in human iPSC-derived neurons from AD patients. Furthermore, pharmacological suppression of RyR-Ca2+ release rescued proteolytic function, revealing a target for therapeutic intervention that has demonstrated effects in clinically-relevant assays.

Inhibition Of Tau Protein Aggregation By a Chaperone-like β-Boswellic Acid Conjugated To Gold Nanoparticles

A potential therapeutic strategy to inhibit tau protein aggregation in neurons has substantial effects on preventing or controlling Alzheimer’s disease (AD). In this work, we designed a covalent and noncovalent conjugation of β-boswellic acid (BA) to gold nanoparticles (GNPs). We provided the opportunity to investigate the effect of the surface composition of BA-GNPs on the aggregation of the tau protein 1N/4R isoform in vitro. HR-TEM and FESEM micrographs revealed that GNPs were spherical and uniform, smaller than 25 nm. According to UV–visible and FTIR data, BA was successfully conjugated to GNPs. The finding illustrates the effect of the surface charge, size, and hydrophobicity of BA-GNPs on the kinetics of tau protein aggregation. The size and surface area of U-G-BA demonstrated that inhibited tau aggregation more effectively than covalently linked BA. The proposed method for preventing tau aggregation was monomer reduction. At the same time, a chaperone-like feature of GNP-BA while sustaining a tau native structure prevented the additional formation of fibrils. Overall, this study provides insight into the interaction of GNP-BAs with a monomer of tau protein and may suggest novel future therapies for AD.

Lignin-carbohydrate complexes suppress SCA3 neurodegeneration via upregulating proteasomal activities

Lignin-carbohydrate complexes (LCCs) represent a group of macromolecules with diverse biological functions such as antioxidative properties. Polyglutamine (polyQ) diseases such as spinocerebellar ataxia type 3 (SCA3) comprise a set of neurodegenerative disorders characterized by the formation of polyQ protein aggregates in patient neurons. LCCs have been reported to prevent such protein aggregation. In this study, we identified a potential mechanism underlying the above anti-protein aggregation activity. We isolated and characterized multiple LCC fractions from bamboo and poplar and found that lignin-rich LCCs (BM-LCC-AcOH and PR-LCC-AcOH) effectively eliminated both monomeric and aggregated mutant ataxin-3 (ATXN3polyQ) proteins in neuronal cells and a Drosophila melanogaster SCA3 disease model. In addition, treatment with BM-LCC-AcOH or PR-LCC-AcOH rescued photoreceptor degeneration in vivo. At the mechanistic level, we demonstrated that BM-LCC-AcOH and PR-LCC-AcOH upregulated proteasomal activity. When proteasomal function was impaired, the ability of the LCCs to suppress ATXN3polyQ aggregation was abolished. Thus, we identified a previously undescribed proteasome-inducing function of LCCs and showed that such activity is indispensable for the beneficial effects of LCCs on SCA3 neurotoxicity.