This page organizes the diverse mechanisms of neurodegeneration into coherent categories and pathway frameworks. Understanding mechanism categories helps identify shared biology across diseases and prioritize therapeutic targets. [@mechanistic2023]
Neurodegenerative mechanisms can be grouped into several major categories: protein aggregation, cellular quality control, inflammation, metabolism, and synaptic dysfunction. [@protein2022]
--- [@neuroinflammation2023]
Amyloid Pathways [@mitochondrial2022]
Tau Pathways
Synuclein Pathways
TDP-43 Pathways
| Mechanism | Key Players | Therapeutic Approach |
|---|---|---|
| Autophagy | mTOR, ULK1, Atg proteins | Activators |
| Proteasome | Ubiquitin, 26S complex | Enhancers |
| ER-associated degradation | Sel1L, HRD1 | Modulators |
| Molecular chaperones | Hsp70, Hsp90 | Inducers |
| Mechanism | Key Players | Therapeutic Approach |
|---|---|---|
| Mitophagy | PINK1, PARKIN | Activators |
| Mitochondrial dynamics | Drp1, Mfn1/2, OPA1 | Modulators |
| Mitochondrial biogenesis | PGC-1alpha | Activators |
| Mitochondrial transfer | Tunneling nanotubes | Enhancement |
Disease-Associated Microglia (DAM)
Pro-inflammatory Pathways
A1 (Neurotoxic) Astrocytes
A2 (Neuroprotective) Astrocytes
| Pathway | Dysfunction | Therapeutic |
|---|---|---|
| Glycolysis | Reduced | Metabolic enhancers |
| TCA cycle | Impaired | Co-factor supplementation |
| OXPHOS | Defective | Mitochondrial modulators |
| Fatty acid oxidation | Reduced | Metabolic shift |
Many mechanisms are shared across neurodegenerative diseases:
| Mechanism | AD | PD | ALS | FTD |
|---|---|---|---|---|
| Protein aggregation | Yes | Yes | Yes | Yes |
| Mitochondrial dysfunction | Yes | Yes | Yes | Yes |
| Neuroinflammation | Yes | Yes | Yes | Yes |
| Synaptic loss | Yes | Yes | Yes | Yes |
| Oxidative stress | Yes | Yes | Yes | Yes |
| Modification | Function | Role in Neurodegeneration |
|---|---|---|
| DNA methylation | Gene silencing | Altered in AD, PD |
| 5-hmC (hydroxymethylation) | Active demethylation | Reduced in AD |
| Histone acetylation | Gene activation | Dysregulated in several disorders |
| Type | Example | Disease Association |
|---|---|---|
| microRNA | miR-29, miR-124 | AD, PD |
| siRNA | Various | Target validation ongoing |
| lncRNA | MALAT1, NEAT1 | Neuroinflammation |
| Branch | Activation | Therapeutic Target |
|---|---|---|
| IRE1 | Accumulation of misfolded proteins | XBP1 splicing modulators |
| PERK | eIF2α phosphorylation | Integrated stress response |
| ATF6 | ER stress | ATF6 activators |
Understanding mechanism categories enables:
| Interaction | Mechanism | Therapeutic Potential |
|---|---|---|
| Microglia-neuron | TREM2 signaling | Agonists in development |
| Astrocyte-neuron | Metabolic coupling | Neuroprotective factors |
| Oligodendrocyte-neuron | Myelin maintenance | Remyelination strategies |
| Mechanism | Description | Biomarkers |
|---|---|---|
| Network hypersynchrony | Excessive neuronal synchronization | EEG, MEG |
| Oscillation disruption | Abnormal brain rhythms | Sleep EEG |
| Functional connectivity loss | Decreased inter-regional connectivity | fMRI |
| Component | Dysfunction | Disease Association |
|---|---|---|
| Blood-brain barrier | Increased permeability | AD, MS |
| Cerebral blood flow | Reduced perfusion | Vascular cognitive impairment |
| Neurovascular unit | Coupling breakdown | AD, PD |
| System | Role | Therapeutic Target |
|---|---|---|
| Chaperone networks | Protein folding | Hsp90/70 modulators |
| Autophagy-lysosomal | Protein clearance | mTOR inhibitors |
| Ubiquitin-proteasome | Targeted degradation | UPS enhancers |
| ER-associated degradation | Misfolded protein clearance | SEL1L modulators |
| Target Combination | Rationale | Example |
|---|---|---|
| Anti-aggregation + Anti-inflammatory | Multiple pathway inhibition | AD trials |
| Mitochondrial + Metabolic | Energy deficit correction | PD trials |
| Synaptic + Neurotrophic | Restore neuronal function | Multiple disorders |
The circadian system plays a crucial role in brain health, and its disruption contributes to neurodegeneration:
| Component | Role in Neurodegeneration | Therapeutic Approach |
|---|---|---|
| Suprachiasmatic nucleus | Master clock dysfunction | Light therapy, chronobiotics |
| BMAL1/CLOCK | Circadian gene dysregulation | SIRT1 modulators |
| Melatonin signaling | Antioxidant, sleep regulation | Melatonin agonists |
| Sleep-wake cycles | Protein clearance enhancement | Sleep optimization |
| Component | Dysfunction | Disease Association |
|---|---|---|
| Sympathetic overactivity | α-synuclein spread | PD, MSA |
| Parasympathetic dysfunction | Gastrointestinal symptoms | PD prodrome |
| Cardiovascular dysregulation | Orthostatic hypotension | Multiple system atrophy |
| Enteric nervous system | Lewy body formation | PD |
| Mechanism Category | Key Pathways | Therapeutic Targets |
|---|---|---|
| Amyloidogenic | APP processing, Aβ production | BACE inhibitors, antibodies |
| Tauopathy | Hyperphosphorylation, propagation | Anti-tau antibodies, kinase inhibitors |
| Neuroinflammation | Microglial activation, complement | TREM2 agonists, NLRP3 inhibitors |
| Metabolic | Insulin resistance, glucose dysregulation | GLP-1 analogs, metabolic modulators |
| Mechanism Category | Key Pathways | Therapeutic Targets |
|---|---|---|
| α-Synucleinopathy | Aggregation, spreading | Immunotherapies, aggregation inhibitors |
| Mitochondrial dysfunction | Complex I deficiency, PINK1/Parkin | Mitochondrial antioxidants |
| Neuroinflammation | Microglial activation, TNF-α | Minocycline, microglial inhibitors |
| Neurotransmitter loss | Dopaminergic cell death | GDNF, cell replacement |
| Mechanism Category | Key Pathways | Therapeutic Targets |
|---|---|---|
| Protein aggregation | TDP-43, SOD1 | ASOs, gene silencing |
| Excitotoxicity | Glutamate, AMPA receptors | Riluzole, perampanel |
| Mitochondrial dysfunction | Energy failure, ROS | Edaravone, metabolic support |
| Neuroinflammation | Microglial activation | Ibudilast, colony-stimulating factors |
| Mechanism Category | Key Pathways | Therapeutic Targets |
|---|---|---|
| Tau pathology | MAPT mutations, tau aggregation | Anti-tau therapies |
| TDP-43 pathology | C9orf72, TARDBP mutations | Gene therapy approaches |
| Neuroinflammation | Microglial activation | Immunomodulation |
| Synaptic dysfunction | PSD95, synaptophysin loss | Synaptic protectors |
Glial activation:
NLRP3 pathway:
Key processes:
Sources:
Processes:
Systems affected: