This page organizes neurodegenerative disease-related proteins into families and functional clusters, enabling analysis of target coverage, identification of redundant functions, and understanding of pathway relationships. Protein family analysis helps prioritize targets and predict off-target effects.
Protein families arise from gene duplication and divergence, with members often sharing structural features and biochemical functions. In neurodegenerative diseases, multiple family members may be involved in pathogenesis, offering both therapeutic opportunities and challenges.
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¶ Amyloid and APP Family
| Protein | Gene | Function | Disease Relevance |
|---------|------|----------|------------------|
| APP | APP | Amyloid precursor | AD causal (mutations) |
| APLP1 | APLP1 | APP-like protein 1 | Possible compensatory |
| APLP2 | APLP2 | APP-like protein 2 | May substitute for APP |
The APP family is central to AD pathogenesis. APP is cleaved by BACE1 and gamma-secretase to produce amyloid-beta. APLP proteins have overlapping functions but do not produce amyloid-beta, suggesting functional redundancy that could be therapeutically exploited.
| Protein |
Gene |
Isoforms |
Function |
| 3R tau |
MAPT |
3 repeat |
Developmental isoforms |
| 4R tau |
MAPT |
4 repeat |
Adult isoforms |
| 2N4R tau |
MAPT |
Full-length |
Most common in AD |
Different tauopathies are characterized by different isoform ratios:
- 3R tauopathies: Pick's disease
- 4R tauopathies: CBD, PSP, AGD
- 3R+4R tauopathies: AD, chronic traumatic encephalopathy
| Protein |
Gene |
Expression |
Function |
| Alpha-synuclein |
SNCA |
Neurons |
Synaptic vesicle regulation |
| Beta-synuclein |
SNCB |
Neurons |
May inhibit aggregation |
| Gamma-synuclein |
SNCG |
Peripheral |
Cancer association |
Beta-synuclein may protect against alpha-synuclein aggregation, suggesting that enhancing beta-synuclein or blocking gamma-synuclein could be therapeutic strategies.
| Protein |
Gene |
Function |
AD Relevance |
| APOE |
APOE |
Lipid transport |
Major risk gene |
| APOJ/CLU |
CLU |
Chaperone |
Risk gene |
| APOA1 |
APOA1 |
HDL component |
Protective signals |
| APOD |
APOD |
Lipid transport |
Neuroprotective |
- APOE ε2: Protective, associated with longevity
- APOE ε3: Most common, neutral risk
- APOE ε4: Major risk factor, ~40% of AD patients
| Family |
Genes |
Function |
Drug Target |
| NMDA |
GRIN1, GRIN2A-D |
Excitotoxicity |
Memantine |
| AMPA |
GRIA1-4 |
Fast transmission |
Perampanel |
| Kainate |
GRIK1-5 |
Modulatory |
Investigational |
| Family |
Genes |
Function |
Drug Target |
| mGluR1 |
GRM1 |
Group I |
CTE therapeutic |
| mGluR5 |
GRM5 |
Group I |
mGluR5 negative allosteric modulators |
| mGluR2/3 |
GRM2, GRM3 |
Group II |
Neuroprotective |
| mGluR4 |
GRM4 |
Group III |
Parkinson's |
| Kinase Family |
Key Members |
Function |
Therapeutic Status |
| CDK |
CDK2, CDK5 |
Cell cycle, tau phos |
Research |
| GSK |
GSK3A, GSK3B |
Tau phosphorylation |
Research |
| MAPK |
ERK1/2, JNK, p38 |
Stress response |
Research |
| LRRK |
LRRK2 |
Synaptic function |
Clinical trials |
Kinase inhibitors face challenges:
- Broad specificity may cause off-target effects
- Adaptive feedback mechanisms
- Blood-brain barrier penetration
| Protease |
Gene |
Cleavage |
Therapeutic Target |
| BACE1 |
BACE1 |
Beta-secretase |
Failed (toxicity) |
| Gamma-secretase |
PSEN1/2 |
Gamma-secretase |
Failed (toxicity) |
| Alpha-secretase |
ADAM10 |
Alpha-secretase |
Protective |
| Protease |
Gene |
Function |
Disease Role |
| Calpain |
CAPN1/2 |
Calcium-activated |
Neurodegeneration |
| Caspases |
CASP3, CASP6 |
Apoptosis |
Executioners |
| MMPs |
MMP2, MMP9 |
Extracellular matrix |
Neuroinflammation |
| HSP Family |
Members |
Function |
Therapeutic |
| Hsp70 |
HSPA1A, HSPA8 |
Chaperone |
Inducers in trials |
| Hsp90 |
HSP90AA1 |
Folding complex |
Inhibitors |
| Small HSPs |
HspB1, alpha-B crystallin |
Aggregation prevention |
Research |
| Component |
Genes |
Function |
| E1 ubiquitin-activating |
UBA1, UBA2 |
Activation |
| E2 ubiquitin-conjugating |
Multiple |
Transfer |
| E3 ubiquitin-ligases |
PARKIN, FBXO7 |
Specificity |
| Deubiquitinases |
Multiple |
Removal |
- Amyloid family
- Tau family
- Synuclein family
- Glutamate receptors
- Synaptic proteins
- Ion channels