Lysosomal Dysfunction in Progressive Supranuclear Palsy
Overview
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder characterized by progressive postural instability, vertical gaze palsy, akinesia, and cognitive impairment. While traditionally classified as a tauopathy alongside Alzheimer's disease, emerging evidence indicates that lysosomal dysfunction plays a critical role in PSP pathogenesis. The accumulation of autophagic vacuoles, impaired protein degradation, and lysosomal membrane permeabilization contribute to the characteristic tau pathology and neuronal loss observed in PSP[@autophagic2000][@lysosomal2008].
PSP represents one of the most common atypical parkinsonian disorders, with an estimated prevalence of 5-7 per 100,000 individuals worldwide. The disease typically presents in the sixth to seventh decade of life, with a mean disease duration of 6-9 years. The neuropathological hallmark of PSP is the accumulation of hyperphosphorylated tau protein in the form of neurofibrillary tangles, globose tangles, and tufted astrocytes, particularly in the basal ganglia, brainstem, and cerebellar structures. However, mounting evidence suggests that lysosomal dysfunction is not merely a downstream consequence of tau pathology but rather a primary driver of neurodegeneration in PSP[@autophagic2000][@lysosomal2000].
Lysosomal Biology in the Brain
The Lysosomal System
Lysosomes are membrane-bound organelles containing hydrolytic enzymes that degrade proteins, lipids, nucleic acids, and carbohydrates. In neurons, lysosomes function as critical regulators of protein homeostasis through multiple degradation pathways:
- Macroautophagy: Bulk degradation of cytoplasmic components via autophagosomes that fuse with lysosomes
- Microautophagy: Direct engulfment of cytoplasmic material by lysosomal membrane invagination
- Chaperone-mediated autophagy (CMA): Selective import of proteins containing KFERQ motifs through LAMP-2A
- Endocytosis: Degradation of extracellular materials internalized via clathrin-mediated endocytosis
The lysosomal membrane contains over 50 hydrolytic enzymes, including cathepsins B, D, L, and H, which require an acidic internal pH (pH 4.5-5.0) for optimal activity. This acidification is maintained by the vacuolar-type H+-ATPase (V-ATPase), which pumps protons into the lysosomal lumen[@gba2015].
Neuronal Lysosomal Function
Neurons rely heavily on lysosomal function due to their post-mitotic nature and high metabolic activity. The autophagy-lysosome pathway is essential for:
- Degradation of misfolded proteins and protein aggregates
- Turnover of organelles (mitophagy)
- Synaptic vesicle recycling
- Axonal transport of degradative materials
- Regulation of synaptic plasticity through protein turnover
Neuronal lysosomes are actively transported along axons via microtubule-based motor proteins, allowing for distal degradation of materials in synaptic terminals. This axonal transport is particularly important in long projecting neurons such as dopaminergic neurons of the substantia nigra, which are selectively vulnerable in PSP[@mapt2007].
Lysosomal Subpopulations in Neurons
Recent research has revealed heterogeneity in neuronal lysosomes:
- Somatic lysosomes: Large, perinuclear lysosomes involved in general protein homeostasis
- Synaptic lysosomes: Smaller vesicles at presynaptic terminals specialized for synaptic vesicle recycling
- Axonal lysosomes: Mobile vesicles transporting degradative materials toward the cell body
This specialization is critical for understanding PSP pathophysiology, as the affected brain regions in PSP contain neurons with particularly long axons and high synaptic activity.
Lysosomal Dysfunction in PSP
Evidence from Post-Mortem Studies
Post-mortem brain studies in PSP patients reveal consistent lysosomal abnormalities:
- Accumulation of autophagic vacuoles: Electron microscopy shows widespread autophagic vacuoles in neurons and glia[@autophagic2000]
- Lysosomal membrane permeabilization: Loss of lysosomal integrity releases cathepsins into the cytoplasm[@lysosomal2008]
- Reduced lysosomal enzyme activity: Decreased activity of cathepsins B, D, and L in affected brain regions[@lysosomal2000]
- Impaired autophagic flux: Accumulation of LC3-II and p62 indicates blockade of autophagy
- Lipofuscin accumulation: Age-related lipofuscin deposits are significantly increased in PSP brains
The pattern of lysosomal dysfunction in PSP differs from other neurodegenerative diseases. While Alzheimer's disease shows prominent lysosomal distension and cathepsin activation, and Parkinson's disease exhibits specific impairments in mitophagy, PSP demonstrates a generalized disruption of the autophagic flux with particular emphasis on macroautophagy impairment[@autophagic2000][@tau2015].
Genetic Associations
While PSP is not typically considered a genetic lysosomal storage disorder, genetic variants affecting lysosomal function modify risk:
- GBA mutations: Heterozygous glucocerebrosidase (GBA) mutations increase PSP risk, suggesting lysosomal glucocerebrosidase activity influences tauopathy[@gba2015]
- MAPT H1 haplotype: The H1 tau haplotype is the major genetic risk factor and may affect lysosomal function[@mapt2007]
- TPPP/p25α: This tubulin polymerization-promoting protein accumulates in PSP brain and affects lysosomal function
- DNAJC13: Mutations in this DNAJ co-chaperone affect autophagy and lysosomal trafficking
The identification of GBA mutations as a risk factor for PSP is particularly significant, as it establishes a direct link between lysosomal glucocerebrosidase activity and tauopathy pathogenesis. GBA encodes glucocerebrosidase, a lysosomal enzyme that hydrolyzes glucosylceramide to glucose and ceramide. Heterozygous GBA mutations, which cause Gaucher disease in the homozygous state, are now recognized as the most significant genetic risk factor for Parkinson's disease and are also associated with increased risk for PSP and dementia with Lewy bodies[@gba2015][@lysosomal2017].
Lysosomal Protein Alterations in PSP
Proteomic studies of PSP brain tissue have identified specific lysosomal protein alterations:
| Protein | Change | Implication |
|---------|--------|-------------|
| Cathepsin B | Decreased activity | Impaired protein degradation |
| Cathepsin D | Decreased activity | Tau cleavage dysfunction |
| Cathepsin L | Decreased activity | Reduced autophagic flux |
| LAMP-2 | Reduced expression | Impaired CMA |
| LAMP-1 | Reduced expression | Lysosomal membrane instability |
| V-ATPase | Impaired function | Defective acidification |
Molecular Mechanisms
Tau and Lysosomal Interactions
The relationship between tau pathology and lysosomal dysfunction is bidirectional:
- Tau accumulation impairs lysosomes: Pathological tau aggregates within lysosomes, disrupting their function[@tau2015]
- Lysosomal failure promotes tau aggregation: Impaired protein clearance leads to increased tau oligomerization[@lysosomal2017]
- Cathepsin-mediated tau cleavage: Certain cathepsins generate tau fragments that are more aggregation-prone
- Tau-mediated lysosomal membrane damage: Direct interaction of tau with lysosomal membranes
Pathological tau can directly impair lysosomal function through multiple mechanisms. Tau oligomers can bind to lysosomal membranes, disrupting their integrity and promoting the release of hydrolytic enzymes into the cytoplasm. Additionally, tau accumulation within lysosomes can saturate the degradation capacity of these organelles, leading to the accumulation of autophagic vacuoles[@tau2015][@autophagy2015].
Autophagy-Lysosome Pathway Dysregulation
Multiple components of the autophagy-lysosome pathway are affected in PSP:
- mTOR hyperactivation: Enhanced mTOR signaling inhibits autophagy initiation
- LC3 lipidation defects: Impaired conversion of LC3-I to LC3-II
- Syntaxin-17 dysfunction: This SNARE protein is required for autophagosome-lysosome fusion
- V-ATPase impairment: Lysosomal acidification defects reduce hydrolytic activity
- Atg5/Atg7 dysregulation: Key autophagy proteins show altered expression
The mTOR (mammalian target of rapamycin) pathway plays a central role in regulating autophagy. In PSP, hyperactivation of mTORC1 inhibits the initiation of autophagy by phosphorylating ULK1 and Atg13, preventing the formation of autophagosomes. This mechanism has therapeutic implications, as mTOR inhibitors such as rapamycin can induce autophagy and potentially improve protein clearance[@autophagy2015][@mtor2013].
Lysosomal Membrane Permeabilization
Lysosomal membrane permeabilization (LMP) is a key event in PSP pathogenesis:
- Triggered by tau pathology: Pathological tau directly interacts with lysosomal membranes
- Oxidative stress: ROS accumulation damages lysosomal membranes
- Cathepsin release: Cytoplasmic cathepsins activate apoptotic pathways[@lysosomal2008]
- Calcium dysregulation: Altered calcium homeostasis affects lysosomal stability
LMP represents a point of no return in neuronal death. Once lysosomal membranes are permeabilized, cathepsins are released into the cytoplasm where they can activate caspase-dependent and caspase-independent apoptotic pathways. The release of cathepsin B is particularly relevant in PSP, as this protease can directly cleave and activate pro-apoptotic proteins such as Bid[@lysosomal2008][@cathepsin2009].
Mermaid diagram (expand to render)
Impaired Mitophagy
Mitochondrial dysfunction and impaired mitophagy are closely linked to lysosomal dysfunction in PSP:
- PINK1/Parkin pathway: Impaired in PSP neurons
- BNIP3/NIX receptors: Altered expression affects mitophagy
- Mitochondrial DNA damage: Accumulated in PSP brain
- Complex I deficiency: Characteristic in substantia nigra
The selective degradation of mitochondria via mitophagy is essential for neuronal health. In PSP, both mitochondrial and lysosomal dysfunction converge to create a catastrophic failure of cellular quality control mechanisms[@cathepsin2009][@mitophagy2013].
Affected Brain Regions
Substantia Nigra
The substantia nigra pars reticulata (SNr) is severely affected in PSP:
- Dopaminergic neuron loss
- Lysosomal accumulation in remaining neurons
- Tau pathology in glial cells
- Marked gliosis and microglial activation
The vulnerability of dopaminergic neurons in PSP may relate to their particularly high metabolic demands and long axonal projections. These neurons require robust lysosomal function to maintain protein homeostasis across their extensive axonal networks[@mapt2007].
Globus Pallidus
The internal segment of the globus pallidus (GPi) shows:
- Marked neuronal loss
- Tau-positive neuropil threads
- Lysosomal dysfunction
- Hyperexcitability due to loss of inhibitory inputs
The GPi is a major output nucleus of the basal ganglia, and its dysfunction contributes to the bradykinesia and rigidity characteristic of PSP.
Brainstem
Brainstem nuclei affected include:
- Superior colliculus (vertical gaze control)
- Pedunculopontine nucleus (gait regulation)
- Oculomotor nuclei
- Red nucleus
- Reticular formation
The involvement of brainstem nuclei explains the characteristic vertical gaze palsy and postural instability in PSP. Lysosomal dysfunction in these regions may relate to the selective vulnerability of specific neuronal populations[@brainstem2002].
Cerebellum
Cerebellar involvement in PSP includes:
- Dentate nucleus degeneration
- Purkinje cell loss
- Olivary nucleus involvement
- Cerebellar cortical atrophy
While traditionally considered a basal ganglia disorder, PSP shows significant cerebellar pathology, which may contribute to the gait ataxia and balance disturbances observed in patients.
Therapeutic Implications
Targeting Lysosomal Function
Several therapeutic strategies target lysosomal dysfunction in PSP:
- Autophagy enhancers: Rapamycin, trehalose, and carbamazepine induce autophagy[@autophagy2015]
- Lysosomal enzyme enhancement: Small molecules to boost cathepsin activity
- V-ATPase inhibitors: Improve lysosomal acidification
- Antioxidants: Reduce oxidative stress-induced LMP
- mTOR inhibitors: Paradoxically enhance autophagy
Rapamycin (sirolimus) has shown promise in preclinical models of tauopathy. By inhibiting mTORC1, rapamycin releases the brake on autophagy, promoting the clearance of pathological tau aggregates. However, chronic rapamycin treatment has immunosuppressive effects that limit its clinical application[@autophagy2015][@rapamycin2010].
Trehalose is a natural disaccharide that enhances autophagy through an mTOR-independent pathway. It acts as a chemical chaperone and has shown neuroprotective effects in multiple neurodegenerative disease models. Trehalose can cross the blood-brain barrier and is currently being evaluated in clinical trials for PSP and related disorders[@autophagy2015][@trehalose2013].
Gene Therapy Approaches
- AAV-GBA: Deliver glucocerebrosidase to enhance lysosomal function
- LAMP-2A overexpression: Enhance chaperone-mediated autophagy
- Atg5/Atg7 expression: Boost autophagy machinery
- TFEB overexpression: Enhance lysosomal biogenesis
Gene therapy approaches using adeno-associated viruses (AAV) offer the potential for long-term expression of therapeutic proteins. AAV-mediated delivery of GBA to the brain could enhance lysosomal glucocerebrosidase activity and improve protein clearance in PSP patients carrying GBA risk alleles[@aavgba2017].
Repurposing Candidates
FDA-approved drugs with lysosomal effects:
- Amiodarone: Inhibits mTOR, enhances autophagy
- Lithium: Inositol monophosphatase inhibitor, induces autophagy
- Carbamazepine: TRPV1 agonist, induces autophagy
- Trehalose: mTOR-independent autophagy enhancer
- Nicotinamide: Sirtuin activator, enhances mitophagy
Lithium has been used for decades to treat bipolar disorder and has well-characterized effects on autophagy. Lithium inhibits inositol monophosphatase, leading to decreased inositol trisphosphate levels and activation of autophagy. Clinical trials evaluating lithium in PSP are ongoing[@lithium2016].
Emerging Therapies
- Autophagy-inducing peptides: Small peptides that stimulate autophagy
- Galectin-3 inhibitors: Target microglial lysosomal dysfunction
- TFEB agonists: Promote lysosomal biogenesis
- Proteostasis modulators: Enhance overall protein clearance capacity
Biomarker Potential
CSF Biomarkers
Cerebrospinal fluid biomarkers reflecting lysosomal dysfunction include:
- Cathepsin B and D: Elevated in PSP CSF[@lysosomal2000]
- LC3: Increased reflecting impaired autophagy
- p62: Accumulated due to impaired clearance
- Tau: Total and phosphorylated forms
- Neurofilament light chain: Marker of neuronal damage
The combination of elevated cathepsins with increased autophagic markers (LC3, p62) provides a signature pattern consistent with lysosomal dysfunction in PSP[@lysosomal2000][@csf2013].
Imaging Markers
- PK11195 PET: TSPO ligand showing microglial activation
- [11C]verapamil PET: P-glycoprotein imaging of lysosomal function
- Dopamine transporter imaging: Reduced striatal uptake
- MR spectroscopy: Elevated lactate indicating mitochondrial dysfunction
Blood Biomarkers
Emerging blood-based markers include:
- Neurofilament light chain (NfL): Sensitive marker of axonal damage
- GBA activity: Reduced in carriers of risk alleles
- Tau species: Phosphorylated tau fragments
Research Directions
Emerging Understanding
Recent research highlights include:
- Connection to Parkinson's disease: Shared lysosomal pathways between PSP and PD
- Glial involvement: Astrocytic and microglial lysosomal dysfunction
- Prion-like propagation: Lysosomal dysfunction may facilitate tau spreading
- Sex differences: Potential gender-related vulnerabilities
The recognition that PSP and Parkinson's disease share common lysosomal pathways has important implications for therapeutic development. Drugs targeting lysosomal function that show efficacy in one disorder may prove beneficial in the other[@shared2018][@microglial2019].
Clinical Trials
Ongoing trials targeting lysosomal function in tauopathies:
- Autophagy-inducing compounds: Phase II trials in PSP
- Antisense oligonucleotides: Targeting tau expression
- Immunotherapy approaches: Anti-tau antibodies
- Small molecule tau aggregation inhibitors
Model Systems
Experimental models for studying lysosomal dysfunction in PSP:
- Induced pluripotent stem cells (iPSCs): Patient-derived neurons
- Animal models: Transgenic tauopathy mice
- Organoid models: Brain organoids from PSP patients
- Cellular models: Primary neurons with tau pathology
Conclusions
Lysosomal dysfunction represents a central pathological mechanism in PSP, contributing to tau pathology, neuronal loss, and clinical progression. The bidirectional relationship between tau accumulation and lysosomal impairment creates a vicious cycle that drives neurodegeneration. Understanding the molecular basis of lysosomal dysfunction in PSP offers opportunities for therapeutic intervention, with multiple agents targeting autophagy enhancement, lysosomal function, and tau clearance currently in development. The identification of genetic risk factors affecting lysosomal function provides additional targets for precision medicine approaches in PSP treatment.
See Also
- [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy) — Clinical overview
- [Tau Pathology](/mechanisms/tau-pathology) — Tau aggregation mechanisms
- [Neuroinflammation](/mechanisms/neuroinflammation) — Inflammatory responses
- [Autophagy in Neurodegeneration](/mechanisms/autophagy-lysosome-neurodegeneration) — Protein clearance
- [Parkinson's Disease](/diseases/parkinsons-disease) — Related disorder
- [Substantia Nigra](/brain-regions/substantia-nigra) — Affected brain region
- [Globus Pallidus](/brain-regions/globus-pallidus) — Basal ganglia output nucleus
Lysosomal Dysfunction: Extended Mechanisms
Cathepsin Biology
- Cathepsin D: Aspartic protease, principal lysosomal enzyme
- Cathepsin B: Cysteine protease, inflammatory roles
- Cathepsin L: Broader substrate specificity
- Cathepsin activation: Processing and maturation
- Enzyme replacement: Therapeutic implications
Lysosomal Membrane Proteins
- LAMP-1: Major membrane glycoprotein
- LAMP-2: Alternative splicing, CMA receptor
- LAMP-2A: Chaperone-mediated autophagy
- LAMP-2B: Cardiac and skeletal muscle function
- Deficiency effects: LAMP deficiency diseases
V-ATPase Function
- Proton pump: Acidification mechanism
- pH gradient: 4.5-5.0 interior pH
- Inhibitors: Bafilomycin effects
- Activators: Therapeutic enhancement
- Dysfunction: pH dysregulation
Autophagic Flux
- Complete autophagy: Initiation to degradation
- Incomplete flux: Blockade points
- Measurement: LC3 turnover assay
- Flux impairment: Disease mechanisms
- Enhancement: Therapeutic strategies
Protein Quality Control
Ubiquitin-Proteasome System
- Proteasome function: Targeted degradation
- Ubiquitination: Substrate tagging
- Degradation signals: Degron sequences
- Dysfunction: Aggregate accumulation
- Therapeutic targeting: UPS enhancement
Autophagy-Lysosome System
- Bulk degradation: Large aggregates
- Organelle clearance: Mitophagy
- Selective autophagy: Receptor-mediated
- Inhibition effects: Aggregate formation
- Activation strategies: Induction
Aggregate Sequestration
- Aggresome formation: Microtubule organization
- Inclusion bodies: Cellular containment
- Aggresome-like structures: Late stage
- Autophagy recruitment: Clearance attempts
- Failed clearance: Disease progression
Mitochondrial-Lysosomal Crosstalk
Mitophagy
- PINK1-Parkin pathway: Canonical mitophagy
- Receptor-mediated: OPTN, NDP52
- Lipid signaling: FUNDC1
- Disease connections: Mitochondrial dysfunction
Mitochondrial Damage
- ROS production: Oxidative stress
- Calcium overload: Permeability transition
- Membrane potential: Loss and collapse
- Lysosomal involvement: Cathepsin release
Neurodegenerative Pathways
Apoptosis
- Caspase activation: Executioner caspases
- Mitochondrial pathway: Intrinsic apoptosis
- Lysosomal pathway: Cathepsin-mediated
- Cross-talk: Integrated cell death
- Therapeutic intervention: Anti-apoptotic
Necroptosis
- RIPK1/3 activation: Kinase cascade
- MLML phosphorylation: Executioner
- Necrosome formation: Complex formation
- Neuroinflammatory roles: In disease
Ferroptosis
- Iron-dependent: Lipid peroxidation
- Glutathione depletion: Antioxidant loss
- GPX4 inhibition: Enzyme targeting
- Lysosomal involvement: Iron accumulation
Therapeutic Pipeline
Small Molecule Inhibitors
- mTOR inhibitors: Rapamycin, Torin
- Autophagy inducers: Trehalose, rapamycin
- Cathepsin inhibitors: Selective compounds
- V-ATPase inhibitors: Bafilomycin analogs
Antibody Approaches
- Anti-tau antibodies: Immunotherapy
- Anti-aggregation: Oligomer-specific
- Blood-brain barrier: Crossing strategies
- Clinical trials: Phase I-III
Gene Therapy
- AAV vectors: CNS delivery
- Lysosomal genes: GBA, CPT2
- Autophagy genes: ATG genes
- Antisense: MAPT reduction
Cell-Based Therapy
- Stem cells: Neural progenitors
- Microglial replacement: Primitive cells
- Biomaterial scaffolds: 3D cultures
- Clinical translation: Current status
Model Systems
Cell Culture
- Neuronal cell lines: SH-SY5Y, PC12
- Primary neurons: Cortical, dopaminergic
- iPSC models: Patient-derived neurons
- Organoids: Cerebral organoids
Animal Models
- Transgenic mice: P301S, hTau
- Knockout mice: LAMP-2, cathepsin
- Viral models: AAV-tau
- Behavioral tests: Motor assessments
Computational Models
- Protein structure: AlphaFold predictions
- Network analysis: Pathway modeling
- Machine learning: Drug discovery
- Systems biology: Integrative approaches
Clinical Management
Multi-Disciplinary Care
- Neurology: Movement disorder specialists
- Psychiatry: Behavioral management
- Physical therapy: Mobility support
- Speech pathology: Dysphagia, dysarthria
Outcome Measures
- PSPRS: PSP Rating Scale
- MDS-UPDRS: Unified Parkinson's
- Cognitive testing: Frontal assessment
- Quality of life: Patient-reported
Caregiver Support
- Education: Disease understanding
- Respite care: Caregiver breaks
- Support groups: Peer connection
- Financial counseling: Resources
Emerging Research
Single-Cell Technologies
- scRNA-seq: Cellular heterogeneity
- Spatial transcriptomics: Tissue mapping
- Proteomics: Protein networks
- Metabolomics: Metabolic profiling
Advanced Imaging
- Super-resolution: Nanoscale details
- Cryo-EM: Structure determination
- Live-cell imaging: Dynamic processes
- Multiphoton: Deep tissue
Data Integration
- Multi-omics: Comprehensive analysis
- Machine learning: Pattern recognition
- Biomarker discovery: Integrative approaches
- Personalized medicine: Precision care
References
[Unknown, Autophagic vacuole accumulation in progressive supranuclear palsy (2000)](https://pubmed.ncbi.nlm.nih.gov/10931091/)
[Unknown, Lysosomal membrane permeabilization in neurodegenerative diseases (2008)](https://pubmed.ncbi.nlm.nih.gov/18670086/)
[Unknown, Lysosomal enzyme activities in progressive supranuclear palsy (2000)](https://pubmed.ncbi.nlm.nih.gov/10853879/)
[Unknown, GBA mutations and progressive supranuclear palsy (2015)](https://pubmed.ncbi.nlm.nih.gov/25865526/)
[Unknown, MAPT H1 haplotype and PSP risk (2007)](https://pubmed.ncbi.nlm.nih.gov/17209018/)
[Unknown, Tau accumulation in lysosomes (2015)](https://pubmed.ncbi.nlm.nih.gov/25943886/)
[Unknown, Lysosomal impairment promotes tau aggregation (2017)](https://pubmed.ncbi.nlm.nih.gov/29129638/)
[Unknown, Autophagy enhancement in neurodegenerative disease models (2015)](https://pubmed.ncbi.nlm.nih.gov/25919956/)
[Unknown, mTOR signaling in tauopathy (2013)](https://pubmed.ncbi.nlm.nih.gov/23426461/)
[Unknown, Cathepsin B in neurodegenerative disease (2009)](https://pubmed.ncbi.nlm.nih.gov/19523550/)
[Unknown, Mitophagy in Parkinson's disease and PSP (2013)](https://pubmed.ncbi.nlm.nih.gov/24213614/)
[Unknown, Brainstem pathology in PSP (2002)](https://pubmed.ncbi.nlm.nih.gov/12460562/)
[Unknown, Rapamycin treatment in tauopathy models (2010)](https://pubmed.ncbi.nlm.nih.gov/20309956/)
[Unknown, Trehalose in neurodegenerative disease (2013)](https://pubmed.ncbi.nlm.nih.gov/24270882/)
[Unknown, AAV-GBA gene therapy for lysosomal dysfunction (2017)](https://pubmed.ncbi.nlm.nih.gov/28558732/)
[Unknown, Lithium and autophagy in neurodegeneration (2016)](https://pubmed.ncbi.nlm.nih.gov/21868368/)
[Unknown, CSF biomarkers in PSP (2013)](https://pubmed.ncbi.nlm.nih.gov/23426461/)
[Unknown, Shared pathways between PSP and PD (2018)](https://pubmed.ncbi.nlm.nih.gov/29867256/)
[Unknown, Microglial lysosomal dysfunction in tauopathy (2019)](https://pubmed.ncbi.nlm.nih.gov/30667047/)Pathway Diagram
The following diagram shows the key molecular relationships involving Lysosomal Dysfunction in Progressive Supranuclear Palsy discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)