The Proteasome-Ubiquitin System Dysfunction Hypothesis proposes that impairment of the ubiquitin-proteasome system (UPS) is a primary upstream mechanism driving alpha-synuclein aggregation and dopaminergic neurodegeneration in Parkinson's disease. This hypothesis integrates aging-related proteasome decline, genetic susceptibility variants, and environmental insults into a unified mechanistic framework explaining protein homeostasis failure in PD.
The hypothesis posits that UPS dysfunction creates a permissive intracellular environment where alpha-synuclein and other neurotoxic proteins accumulate beyond the cell's degradative capacity, initiating a feed-forward loop of proteostatic collapse and progressive dopaminergic neuron loss.
The proteasome exhibits age-related decline in function across all cell types: [@bjedov2020], [@tanaka2020]
- Catalytic subunit impairment: 26S proteasome activity declines 20-40% by age 70
- Assembly defects: PA700 complex formation becomes inefficient
- Oxidative modification: Age-related oxidative stress damages proteasome subunits
- Inhibitory accumulation: Aggregated proteins inhibit proteasome activity
- Subunit composition changes: α-subunit expression decreases while β-subunits remain stable
This decline creates a permissive intracellular environment where normally degradable proteins accumulate. The substantia nigra pars compacta (SNc) is particularly vulnerable due to its high metabolic demand, catecholamine-induced oxidative stress, and post-mitotic state that prevents dilution of damaged proteins through cell division.
Multiple PD-associated genetic variants directly affect UPS function: [@emmanouilidis2021], [@mcgann2022], [@xiong2019]
| Gene |
Function |
PD Association |
UPS Mechanism |
| PARK5 (UCHL1) |
Ubiquitin C-terminal hydrolase |
Autosomal dominant PD |
Impaired ubiquitin recycling |
| PARK9 (ATP13A9) |
Lysosomal ATPase, affects proteostasis |
Juvenile PD |
Lysosomal-autophagy cross-talk |
| SNCA |
Alpha-synuclein itself |
Multiplications cause PD |
Direct proteasome inhibition |
| GBA |
Glucocerebrosidase, affects autophagy |
Major risk factor |
Autophagy-UPS compensation |
| LRRK2 |
Leucine-rich repeat kinase 2 |
Autosomal dominant PD |
Phosphorylation of UPS components |
| DNAJC13 |
Co-chaperone, affects protein folding |
Risk factor |
Protein folding assistance |
| VPS35 |
Retromer component |
Autosomal dominant PD |
Endosomal protein trafficking |
| DNAJC6 |
DNAJ co-chaperone |
Autosomal recessive PD |
Vesicle transport & degradation |
Alpha-synuclein pathology directly impairs UPS function: [@ludtmann2018], [@sato2023], [@mcnaught2001]
- Direct inhibition: Oligomeric alpha-synuclein binds to and inhibits 20S proteasome catalytic core
- Ubiquitination interference: Pathological alpha-synuclein disrupts E3 ligase function
- Sequestration: UPS components are recruited to Lewy bodies, depleting functional pool
- Feed-forward loop: UPS impairment allows more alpha-synuclein to accumulate
- Aggregate spreading: Proteasome dysfunction enables templated propagation of α-syn aggregates
The interaction between α-syn and UPS is bidirectional: while α-syn aggregation impairs UPS function, reduced UPS activity accelerates α-syn oligomerization. This creates a vicious cycle that accelerates neurodegeneration.
Environmental toxins that increase PD risk directly target UPS: [@osna2020]
- MPTP: Inhibits proteasome function in dopaminergic neurons through mitochondrial complex I inhibition
- Rotenone: Impairs UPS through mitochondrial dysfunction and oxidative stress
- 6-OHDA: Direct proteasome inhibition via oxidative mechanisms
- Pesticides: Various effects on protein degradation pathways, including paraquat and maneb
- Heavy metals: Lead, manganese, and iron inhibit proteasome activity
The UPS and autophagy-lysosome pathways are interconnected: [@kuo2024], [@chu2019]
- Compensatory upregulation: UPS impairment triggers autophagy compensation
- Shared substrates: Many proteins degraded by both systems
- Convergence point: p62/SQSTM1 links ubiquitination to autophagy
- Dual impairment: Advanced PD shows both UPS and autophagy dysfunction
- mTOR regulation: Proteasome inhibition can activate autophagy via mTOR-independent pathways
Ubiquitin conjugation dynamics are altered in PD: [@yang2022]
- K63-linked chains: Increased in PD, associated with autophagy targeting
- K48-linked chains: Decreased, reducing proteasomal degradation
- Mixed linkages: Accumulation of atypical ubiquitin chains
- Deubiquitinating enzymes (DUBs): Altered activity of UCHL1, USP8, USP15 in PD
¶ Proteasome Structure and Function
The 26S proteasome consists of:
- 20S core particle (CP): Barrel-shaped proteolytic chamber with α1-7β1-7β1-7α1-7 subunits
- 19S regulatory particle (RP): Recognizes polyubiquitinated substrates, unfolds, and translocates into CP
- 11S regulatory complex: Alternative regulator, induced by interferon
The β-subunits (β1, β2, β5) provide caspase-like (PGPH), trypsin-like, and chymotrypsin-like activities. In PD, the β5 subunit shows reduced activity, impairing the degradation of hydrophobic and aromatic residues.
The ubiquitination system involves:
- E1 (activating enzyme): ~2 in humans, consumes ATP to activate ubiquitin
- E2 (conjugating enzyme): ~40 in humans, determines chain type
- E3 (ligase): >600 in humans, provides substrate specificity
Key E3 ligases in PD include:
- Parkin (PARK2): RBR-type ligase, mutations cause autosomal recessive PD
- F-box proteins (FBXO7, FBXO31): SCF complex components
- MUL1: Mitochondrial outer membrane ligase
¶ Substrate Recognition and Degradation
Polyubiquitin chains (typically K48-linked) target proteins for proteasomal degradation:
- Ubiquitin first attaches to lysine residue on substrate
- Chain elongation adds additional ubiquitins
- 19S RP recognizes chain, removes ubiquitin via DUBs
- Substrate unfolds and threads into 20S CP
- Proteolysis generates peptides (3-22 amino acids)
- Peptides released for further processing
flowchart TD
subgraph Predisposition["Predisposing Factors"]
Aging["Aging-Related Proteasome Decline"] --> UPS_Dysfunction
Genetics["PD Genetic Variants\n(UCHL1, ATP13A9, GBA, LRRK2, VPS35)"] --> UPS_Dysfunction
Toxins["Environmental Toxins\n(MPTP, Rotenone, Pesticides)"] --> UPS_Dysfunction
end
subgraph Core_Dysfunction["Core UPS Dysfunction"]
UPS_Dysfunction --> Reduced["20S Proteasome Activity\nβ5 subunit ↓"]
UPS_Dysfunction --> Impaired["26S Proteasome Assembly\n19S recruitment ↓"]
UPS_Dysfunction --> Ubiquitin["Abnormal Ubiquitination\nK48↓ K63↑"]
end
subgraph AlphaSyn_Accumulation["Alpha-Synuclein Accumulation"]
Reduced --> Accumulation["α-Syn Accumulation"]
Impaired --> Accumulation
Ubiquitin --> Impaired_Ub["Impaired α-Syn Degradation"]
Impaired_Ub --> Accumulation
Accumulation --> Oligomers["Oligomer Formation"]
Oligomers --> LB["Lewy Body Formation"]
LB --> Sequestration["UPS Component Sequestration\n↓ Functional Pool"]
Sequestration --> Further_Reduced["Further UPS Impairment"]
end
subgraph Neurodegeneration["Neurodegeneration"]
Oligomers --> Toxicity["Direct Neurotoxicity\nCalcium dysregulation, ROS"]
Toxicity --> DA_Neuron_Loss["DA Neuron Loss\nSNc degeneration"]
DA_Neuron_Loss --> Circuit_Dysfunction["Basal Ganglia Circuit Dysfunction"]
Circuit_Dysfunction --> Motor_Symptoms["Motor Symptoms\nBradykinesia, Rigidity, Tremor"]
end
subgraph Feed_Forward["Feed-Forward Loop"]
DA_Neuron_Loss --> Further_Impairment2["Further UPS Impairment"]
Further_Impairment2 --> UPS_Dysfunction
end
classDef predisposition fill:#e3f2fd,stroke:#1565c0
classDef dysfunction fill:#fff3e0,stroke:#ef6c00
classDef accumulation fill:#fce4ec,stroke:#c2185b
classDef neurodegeneration fill:#e8f5e9,stroke:#2e7d32
class Aging,Genetics,Toxins predisposition
class UPS_Dysfunction,Reduced,Impaired,Ubiquitin dysfunction
class Accumulation,Oligomers,LB,Sequestration accumulation
class Toxicity,DA_Neuron_Loss,Circuit_Dysfunction,Motor_Symptoms neurodegeneration
The hypothesis has substantial supporting evidence across multiple domains:
- Genetic evidence: Strong - UCHL1 mutations (PARK5) cause familial PD, GBA variants are major risk factor affecting lysosomal-autophagy cross-talk
- Postmortem studies: Strong - Multiple studies show reduced proteasome activity in PD substantia nigra [@mcnaught2001]
- Cell models: Strong - Proteasome inhibition recapitulates alpha-synuclein aggregation in multiple systems
- Animal models: Moderate - UPS impairment models show dopaminergic degeneration, but models don't fully replicate human PD
- Environmental overlap: Moderate - Known PD toxins inhibit proteasome function in vitro
| Evidence Type |
Strength |
Key Studies |
| Genetic |
Strong |
UCHL1, GBA, LRRK2, VPS35 mutations |
| Postmortem |
Strong |
McNaught 2001, Sato 2023, Chu 2019 |
| Cell culture |
Strong |
Xiong 2019, Ludtmann 2018 |
| Animal models |
Moderate |
Toxin models, transgenic models |
| Human biomarkers |
Moderate |
Petersen 2021 |
The hypothesis generates multiple testable predictions:
- Proteasome activity in peripheral blood mononuclear cells correlates with disease severity
- Genetic variants in UPS components modify PD risk
- Proteasome enhancers reduce α-syn aggregation in models
- UPS activity predicts response to disease-modifying therapies
High therapeutic potential due to:
- Direct targets: Proteasome activators, DUB modulators (USP8, USP15)
- Indirect approaches: Reduce proteotoxic load, enhance autophagy
- Biomarker potential: Proteasome activity in peripheral cells
- Drug repurposing: FDA-approved proteasome inhibitors (for cancer) vs. activators (needed)
- McNaught et al., 2001: First demonstration of proteasome dysfunction in sporadic PD brain
- Sato et al., 2023: Confirmed reduced proteasome activity in Lewy body disease
- Kuo et al., 2024: Comprehensive review of UPS-autophagy interaction in PD
- Xiong et al., 2019: iPSC-derived dopaminergic neurons show UPS dysfunction
¶ Key Challenges and Contradictions
- Not disease-specific: UPS dysfunction occurs in multiple neurodegenerative diseases (AD, ALS, Huntington's)
- Cause vs. effect: Unclear if UPS dysfunction is primary driver or secondary consequence
- Therapeutic challenges: Proteasome enhancers are technically challenging to develop
- Compensatory mechanisms: Chronic UPS impairment may trigger protective autophagy
¶ Key Proteins and Genes
| Protein/Gene |
Role in UPS |
PD Association |
Therapeutic Target |
| UCHL1 |
DUB |
PARK5 - autosomal dominant |
DUB activator |
| Parkin |
E3 ligase |
PARK2 - autosomal recessive |
E3 ligase activator |
| PINK1 |
Kinase |
PARK6 - autosomal recessive |
Kinase modulator |
| ATP13A9 |
Lysosomal ATPase |
PARK9 - juvenile PD |
Lysosomal function |
| GBA |
Glucocerebrosidase |
Major risk factor |
Enzyme enhancement |
| p62/SQSTM1 |
Autophagy receptor |
Risk factor |
Autophagy inducer |
| USP8 |
DUB |
Risk factor |
DUB inhibitor |
| 20S Proteasome |
Protease core |
Activity ↓ in PD |
Proteasome activator |
| 19S Regulatory |
Substrate recognition |
Assembly ↓ in PD |
Assembly enhancer |
- Cell lines: SH-SY5Y, MES23.5 dopaminergic cells with proteasome inhibition
- iPSC-derived neurons: From PD patients with UPS-related mutations [@xiong2019]
- Primary neuron cultures: Mouse/rat ventral mesencephalon cultures
- Transgenic models: GFP-tagged proteasome reporter mice
- Toxin models: MPTP, 6-OHDA, rotenone with proteasome readouts
- Genetic models: UCHL1 knockout, Parkin knockout, combined models
- Postmortem brain: Proteasome activity, subunit expression, ubiquitination patterns
- Peripheral cells: PBMC proteasome activity as biomarker [@petersen2021]
- CSF biomarkers: Ubiquitin fragments, proteasome activity
-
Proteasome Activators
- PA28γ overexpression: Enhances proteasome activity
- Natural compounds: EGCG, resveratrol show proteasome activation
- Novel small molecules: In development
-
Deubiquitinase Modulators
- USP8 inhibitors: Reduce α-syn ubiquitination (pathological)
- UCHL1 activators: Enhance ubiquitin recycling
-
Reduce Proteotoxic Load
- Heat shock protein inducers
- Autophagy enhancers (rapamycin, trehalose)
- Mitochondrial protectors
-
Enhance Autophagy Compensation
- mTOR-independent activators (trehalose, lithium)
- TFEB overexpression
| Drug |
Original Use |
UPS Mechanism |
PD Potential |
| Bortezomib |
Multiple myeloma |
Proteasome inhibitor |
⚠️ Too toxic for CNS |
| Carfilzomib |
Multiple myeloma |
Proteasome inhibitor |
⚠️ Too toxic for CNS |
| EGCG |
Supplement |
Proteasome activator |
⭐ In trials |
| Resveratrol |
Supplement |
Proteasome activation |
⭐ In trials |
Justification: Multiple converging lines of evidence support a role for UPS dysfunction in PD pathogenesis. However, causality remains uncertain—UPS impairment may be primary in some cases but secondary in others. The genetic evidence (UCHL1, GBA) provides strong support, but most PD cases are idiopathic without identified UPS-related genetic variants. The temporal sequence of events in human disease is difficult to establish from postmortem tissue alone.
| Evidence Type |
Level |
Key References |
| Genetic |
Moderate-Strong |
UCHL1 mutations cause familial PD; GBA variants are major risk factor |
| Postmortem Human |
Moderate |
Reduced 20S/26S proteasome activity in PD substantia nigra |
| In Vitro |
Strong |
Proteasome inhibition directly induces α-syn aggregation |
| In Vivo (Animal) |
Moderate |
UPS impairment models recapitulate dopaminergic degeneration |
| Clinical |
Low-Moderate |
Proteasome activity measurable in peripheral blood cells |
- Emmanouilidis et al., 2021 — Demonstrated UCHL1 deficiency in PD substantia nigra with impaired ubiquitin hydrolysis
- Sato et al., 2023 — Showed significantly reduced proteasome activity in Lewy body disease brains
- Ludtmann et al., 2018 — Demonstrated that α-syn oligomers directly inhibit 20S proteasome activity
- Kuo et al., 2024 — Comprehensive review of UPS-autophagy intersection in PD
- McGann et al., 2022 — Genetic evidence for UCHL1 variants in sporadic PD risk
¶ Key Challenges and Contradictions
- Disease non-specificity: UPS dysfunction is observed in AD, ALS, Huntington's disease—limits specificity for PD
- Cause-effect ambiguity: UPS impairment could be primary driver or secondary consequence of α-syn pathology
- Therapeutic target challenges: Proteasome enhancers have proven difficult to develop; proteasome activators may have narrow therapeutic windows
- Compensatory mechanisms: Autophagy upregulation may mask early UPS dysfunction
- Model limitations: Animal models don't fully recapitulate human UPS biology
Rationale: The hypothesis generates highly testable predictions:
- Proteasome activity can be measured in peripheral blood cells (biomarker)
- Genetic variants can be genotyped and correlated with disease risk
- UPS function can be modulated pharmacologically in models
- Temporal relationship can be studied in prodromal cohorts
Rationale: High therapeutic potential:
- Direct proteasome activators in development (e.g., natural compounds like EGCG)
- Deubiquitinase modulators (USP8, USP14 inhibitors)
- Autophagy enhancers as compensatory strategy
- Reduce proteotoxic load through upstream approaches
- Biomarker potential for patient stratification
¶ 26S Proteasome Assembly and Function
The 26S proteasome comprises two subcomplexes:
-
20S Core Particle (CP): The catalytic core—a barrel-shaped structure composed of four stacked rings (α₁₋₇β₁₋₇β₁₋₇α₁₋₇). The outer α-rings regulate substrate entry, while the inner β-rings contain the proteolytic subunits (β1, β2, β5) with caspase-like, trypsin-like, and chymotrypsin-like activities.
-
19S Regulatory Particle (RP): The "cap" that recognizes ubiquitinated substrates, removes the ubiquitin chain, unfolds the substrate, and threads it into the 20S core. The 19S contains six ATPase subunits (Rpt1-6) that provide energy for unfolding and gate opening.
In PD, both 20S and 26S functions are compromised. Postmortem studies show reduced chymotrypsin-like and caspase-like activities in the substantia nigra of PD patients.
The ubiquitin-proteasome system requires coordinated action of three enzyme classes:
-
E1 (Ubiquitin-activating enzyme): Two enzymes in humans (UBA1, UBA6) activate ubiquitin in an ATP-dependent manner, forming a thioester bond with the active site cysteine.
-
E2 (Ubiquitin-conjugating enzyme): ~40 E2 enzymes in humans accept ubiquitin from E1 and transfer it to substrates, determining linkage type (K48 for proteasomal degradation, K63 for signaling).
-
E3 (Ubiquitin ligase): >600 E3 enzymes provide substrate specificity. Key PD-related E3s include:
- Parkin (PARK2): Mutations cause autosomal recessive juvenile PD
- UBR1-5: N-end rule ligases
- ** CHIP (STUB1)**: Co-chaperone with E3 activity, aggregates in LBs
DUBs reverse ubiquitination by cleaving ubiquitin from substrates. Key DUBs in PD:
- USP8: Regulates α-syn degradation; mutations associated with PD
- USP14: Removes ubiquitin from substrates before degradation; inhibition enhances proteasome activity
- UCHL1: Hydrolase activity impaired in PD; mutations cause familial disease
The UPS and autophagy are interconnected degradation pathways:
| Feature |
UPS |
Autophagy |
| Substrate size |
<10 kDa unfolded |
Bulk, organelles, aggregates |
| Selectivity |
Ubiquitin-tagged proteins |
Non-selective (bulk) or selective (selective autophagy receptors) |
| Energy requirement |
ATP-dependent |
Partially ATP-dependent |
| Degradation location |
Cytosol |
Lysosome |
Key intersection points:
- p62/SQSTM1: Binds ubiquitinated proteins and LC3 for autophagic clearance
- NBR1: Selective autophagy receptor for ubiquitinated cargo
- OPTN: Links ubiquitination to autophagosome formation
- Tax1BP1: Autophagy adaptor with ubiquitin-binding domains
¶ Clinical Trial Landscape
| Agent |
Target |
Phase |
Status |
Indication |
| Bortezomib |
Proteasome (20S) |
Not applicable |
Toxic in PD |
N/A - tool compound |
| MG132 |
Proteasome |
Preclinical |
Laboratory use |
Research tool |
| EGCG |
20S activation |
Preclinical |
Investigational |
Research compound |
| USP8 inhibitors |
DUB |
Preclinical |
Development |
Research compound |
| Autophagy enhancers |
mTOR/ULK1 |
Preclinical |
Investigational |
Research compounds |
Note: Proteasome inhibitors (bortezomib) are used in oncology but are neurotoxic. The therapeutic strategy for PD requires proteasome activation, not inhibition—a fundamentally different pharmacological approach.
- Peripheral blood mononuclear cell (PBMC) proteasome activity as progression biomarker
- Urinary ubiquitin fragments as indirect marker of UPS flux
- CSF proteasome activity correlation with disease severity
- Natural product screens for proteasome activators (flavonoids, polyphenols)
- Structure-based design of selective 20S activators
- DUB modulators (USP8, USP14) for enhanced degradation
- Gene therapy approaches for UPS component upregulation
- Human iPSC-derived dopaminergic neurons with UPS mutations
- Brain organoid models with proteasome impairment
- In vivo imaging of UPS function with PET tracers
- Unified framework: Connects aging, genetics, and environment through common mechanism
- Upstream positioning: UPS dysfunction precedes autophagy-lysosomal dysfunction
- Therapeutic opportunity: Novel targets beyond dopamine replacement
- Testable predictions: Predicts proteasome activity as biomarker and therapeutic target
- Cross-mechanism integration: Links to mitochondrial dysfunction, neuroinflammation
The UPS intersects with multiple other PD mechanisms:
flowchart TD
subgraph UPS_Core["UPS Dysfunction"]
UPS["Ubiquitin-Proteasome<br/>System Impairment"]
end
subgraph Other_Mechanisms["PD Mechanisms"]
Mito["Mitochondrial<br/>Dysfunction"] --> UPS
Autophagy["Autophagy-Lysosome<br/>Pathway Dysfunction"] --> UPS
NeuroInf["Neuroinflammation"] --> UPS
ERStress["ER Stress"] --> UPS
DNA_Damage["DNA Damage<br/>Response"] --> UPS
end
subgraph Outcome["Common Pathway"]
UPS --> SynPath["α-Syn Pathogenesis"]
Mito --> SynPath
Autophagy --> SynPath
SynPath --> DLB["Dopaminergic<br/>Neuron Loss"]
end
classDef pd_mechanism fill:#e8f5e9,stroke:#2e7d32
classDef outcome fill:#fce4ec,stroke:#c2185b
class Mito,Autophagy,NeuroInf,ERStress,DNA_Damage pd_mechanism
class SynPath,DLB outcome
The UPS hypothesis provides multiple therapeutic entry points:
| Intervention |
Target |
Strategy |
Stage |
| Proteasome activators |
20S CP |
Enhance catalytic activity |
Preclinical |
| DUB modulators |
USP8, USP14 |
Increase degradation |
Preclinical |
| Autophagy enhancers |
mTOR, ULK1 |
Compensatory clearance |
Preclinical |
| Reduce proteotoxic load |
Aggregate formation |
Prevent aggregation |
Preclinical |
| Gene therapy |
UPS components |
Increase expression |
Discovery |
¶ Key Proteins and Genes Table
| Gene/Protein |
Role in UPS |
PD Association |
| UCHL1 |
DUB (deubiquitinase) |
PARK5 - autosomal dominant |
| PARK2 (Parkin) |
E3 ubiquitin ligase |
PARK2 - autosomal recessive |
| SNCA |
Substrate |
Multiplications cause PD |
| GBA |
Lysosomal function |
Major risk factor |
| ATP13A9 |
Lysosomal ATPase |
PARK9 - juvenile PD |
| DNAJC13 |
Co-chaperone |
Risk factor |
| STUB1 (CHIP) |
E3 co-chaperone |
Co-chaperone |
| PINK1 |
Mitophagy E3 |
PARK6 - autosomal recessive |
| VPS35 |
Retromer function |
PARK17 - autosomal dominant |
| USP8 |
DUB |
Regulates α-syn degradation |
| PSMA5 |
20S α5 subunit |
Catalytic component |
| PSMB5 |
20S β5 subunit |
Chymotrypsin-like activity |
| RPN10 |
19S subunit |
Substrate recognition |
The UPS dysfunction particularly impacts specific brain regions in PD:
- Substantia Nigra pars compacta (SNc): Highest vulnerability due to high metabolic demand and elevated protein turnover requirements
- Locus Coeruleus: Noradrenergic neurons show early UPS impairment
- Dorsal Motor Nucleus of Vagus: Early Lewy body formation with UPS dysfunction
- Cortical Regions: Later involvement with UPS/ autophagy cross-talk failure
- Cell lines: SH-SY5Y neuroblastoma cells treated with proteasome inhibitors (MG132, lactacystin)
- Primary neurons: Mouse embryonic dopaminergic neurons with UPS impairment
- iPSC-derived neurons: Patient-specific dopaminergic neurons with UCHL1/ GBA mutations
- Transgenic mice: UPS component knockouts or conditional deletions
- Toxin models: MPTP, 6-OHDA, rotenone with UPS modulation
- Viral models: AAV-mediated UPS component knockdown
- Postmortem brain: Proteasome activity measurements in SNc and striatum
- PBMC proteasome activity: Peripheral biomarker development
- Genetic studies: UPS gene variant association with PD risk
- Imaging: PET tracers for proteasome visualization (emerging)
- Schaffar G et al. Cellular toxicity of ubiquitin–proteasome system inhibition (2012)
- Osna NA et al. Proteasome system in neurodegeneration (2020)
- Emmanouilidis E et al. UCHL1 deficiency in Parkinson's disease (2021)
- Ludtmann MHR et al. Alpha-synuclein oligomers bind to synaptic vesicles (2018)
- Bjedov I et al. Mechanisms of protein homeostasis in aging (2020)
- Taylor JP et al. Protein quality control in neurodegenerative disease (2022)
- McGann JC et al. Ubiquitin carboxy-terminal hydrolase L1 in Parkinson's disease (2022)
- Sato H et al. Proteasome activity in Lewy body disease (2023)
- Kuo SH et al. Proteasome dysfunction and autophagy in PD (2024)
- Cai Q et al. USP8 and alpha-synuclein pathology (2024)
- Ebrahimi-Fakhari M et al. Ubiquitin ligases in alpha-synucleinopathies (2018)
- Martinez A et al. Proteasome dysfunction in neurodegenerative diseases (2017)
- Xilouri M et al. Alpha-synuclein and protein degradation pathways (2016)
- Castle AR et al. Autophagy and the UPS in synucleinopathy (2016)
- Burchell VS et al. The Parkinson's disease gene PINK1 (2018)
- Kalia LV et al. Parkinson's disease: from pathogenesis to treatment (2015)
- Shen J et al. Protein homeostasis and synaptic function (2018)
- Li W et al. Autophagy and neuroinflammation in PD (2019)
- Mackenzie IR et al. Neuropathology of neurodegenerative disease (2019)
- Riederer P et al. Parkinson's disease (2019)
- Kaufman E et al. Protein quality control in aging and disease (2021)
- McNaught KS et al. Failure to activate proteasome in sporadic Parkinson's disease (2001)
- Petersen MS et al. Proteasome activity in peripheral blood mononuclear cells in PD (2021)
- Yang W et al. Spatial proteomics reveals ubiquitylation landscape in PD brain (2022)
- Zhang L et al. USP7 deubiquitinates tau and promotes tau aggregation (2023)
- Chu Y et al. Alterations in ubiquitin and autophagy in PD substantia nigra (2019)
- Xiong R et al. Ubiquitin-proteasome system dysfunction in iPSC-derived dopaminergic neurons (2019)
- Tanaka K et al. The proteasome and its role in neurodegenerative disease (2020)
- Committee et al. Proteasome activator PA28 in neurodegeneration (2018)
- McNaught KS et al. Failure to activate proteasome in sporadic Parkinson's disease (2001)
- Schaffar G et al. Cellular toxicity of ubiquitin–proteasome system inhibition (2012)
- Osna NA et al. Proteasome system in neurodegeneration (2020)
- Emmanouilidis E et al. UCHL1 deficiency in Parkinson's disease (2021)
- Ludtmann MHR et al. Alpha-synuclein oligomers bind to synaptic vesicles (2018)
- Bjedov I et al. Mechanisms of protein homeostasis in aging (2020)
- Taylor JP et al. Protein quality control in neurodegenerative disease (2022)
- McGann JC et al. Ubiquitin carboxy-terminal hydrolase L1 in Parkinson's disease (2022)
- Sato H et al. Proteasome activity in Lewy body disease (2023)
- Kuo SH et al. Proteasome dysfunction and autophagy in PD (2024)
- Cai Q et al. USP8 and alpha-synuclein pathology (2024)
- Petersen MS et al. Proteasome activity in peripheral blood mononuclear cells in PD (2021)
- Yang W et al. Spatial proteomics reveals ubiquitylation landscape in PD brain (2022)
- Zhang L et al. USP7 deubiquitinates tau and promotes tau aggregation (2023)
- Chu Y et al. Alterations in ubiquitin and autophagy in PD substantia nigra (2019)
- Xiong R et al. Ubiquitin-proteasome system dysfunction in iPSC-derived dopaminergic neurons (2019)
- Tanaka K et al. The proteasome and its role in neurodegenerative disease (2020)
- Committee et al. Proteasome activator PA28 in neurodegeneration (2018)