Protein Families & Clusters

Protein Families & Clusters

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Protein Families & Clusters</th>
</tr>
<tr>
<td class="label">Protein</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">[APP](/entities/app-protein)</td>
<td>APP</td>
</tr>
<tr>
<td class="label">APLP1</td>
<td>APLP1</td>
</tr>
<tr>
<td class="label">APLP2</td>
<td>APLP2</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">3R tau</td>
<td>[MAPT](/proteins/tau)</td>
</tr>
<tr>
<td class="label">4R tau</td>
<td>MAPT</td>
</tr>
<tr>
<td class="label">2N4R tau</td>
<td>MAPT</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">[Alpha-synuclein](/proteins/alpha-synuclein)</td>
<td>SNCA</td>
</tr>
<tr>
<td class="label">Beta-synuclein</td>
<td>SNCB</td>
</tr>
<tr>
<td class="label">Gamma-synuclein</td>
<td>SNCG</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">[APOE](/proteins/apoe)</td>
<td>APOE</td>
</tr>
<tr>
<td class="label">APOJ/CLU</td>
<td>CLU</td>
</tr>
<tr>
<td class="label">APOA1</td>
<td>APOA1</td>
</tr>
<tr>
<td class="label">APOD</td>
<td>APOD</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Genes</td>
</tr>
<tr>
<td class="label">NMDA</td>
<td>GRIN1, GRIN2A-D</td>
</tr>
<tr>
<td class="label">

Protein Families & Clusters

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Protein Families & Clusters</th>
</tr>
<tr>
<td class="label">Protein</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">[APP](/entities/app-protein)</td>
<td>APP</td>
</tr>
<tr>
<td class="label">APLP1</td>
<td>APLP1</td>
</tr>
<tr>
<td class="label">APLP2</td>
<td>APLP2</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">3R tau</td>
<td>[MAPT](/proteins/tau)</td>
</tr>
<tr>
<td class="label">4R tau</td>
<td>MAPT</td>
</tr>
<tr>
<td class="label">2N4R tau</td>
<td>MAPT</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">[Alpha-synuclein](/proteins/alpha-synuclein)</td>
<td>SNCA</td>
</tr>
<tr>
<td class="label">Beta-synuclein</td>
<td>SNCB</td>
</tr>
<tr>
<td class="label">Gamma-synuclein</td>
<td>SNCG</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">[APOE](/proteins/apoe)</td>
<td>APOE</td>
</tr>
<tr>
<td class="label">APOJ/CLU</td>
<td>CLU</td>
</tr>
<tr>
<td class="label">APOA1</td>
<td>APOA1</td>
</tr>
<tr>
<td class="label">APOD</td>
<td>APOD</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Genes</td>
</tr>
<tr>
<td class="label">NMDA</td>
<td>GRIN1, GRIN2A-D</td>
</tr>
<tr>
<td class="label">AMPA</td>
<td>GRIA1-4</td>
</tr>
<tr>
<td class="label">Kainate</td>
<td>GRIK1-5</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Genes</td>
</tr>
<tr>
<td class="label">mGluR1</td>
<td>GRM1</td>
</tr>
<tr>
<td class="label">mGluR5</td>
<td>GRM5</td>
</tr>
<tr>
<td class="label">mGluR2/3</td>
<td>GRM2, GRM3</td>
</tr>
<tr>
<td class="label">mGluR4</td>
<td>GRM4</td>
</tr>
<tr>
<td class="label">Kinase Family</td>
<td>Key Members</td>
</tr>
<tr>
<td class="label">CDK</td>
<td>CDK2, [CDK5](/proteins/cdk5)</td>
</tr>
<tr>
<td class="label">GSK</td>
<td>GSK3A, [GSK3B](/entities/gsk3-beta)</td>
</tr>
<tr>
<td class="label">MAPK</td>
<td>ERK1/2, JNK, p38</td>
</tr>
<tr>
<td class="label">LRRK</td>
<td>LRRK2</td>
</tr>
<tr>
<td class="label">Protease</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">BACE1</td>
<td>BACE1</td>
</tr>
<tr>
<td class="label">Gamma-secretase</td>
<td>[PSEN1](/entities/psen1)/2</td>
</tr>
<tr>
<td class="label">Alpha-secretase</td>
<td>ADAM10</td>
</tr>
<tr>
<td class="label">Protease</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">Calpain</td>
<td>CAPN1/2</td>
</tr>
<tr>
<td class="label">Caspases</td>
<td>CASP3, CASP6</td>
</tr>
<tr>
<td class="label">MMPs</td>
<td>MMP2, MMP9</td>
</tr>
<tr>
<td class="label">HSP Family</td>
<td>Members</td>
</tr>
<tr>
<td class="label">Hsp70</td>
<td>HSPA1A, HSPA8</td>
</tr>
<tr>
<td class="label">Hsp90</td>
<td>HSP90AA1</td>
</tr>
<tr>
<td class="label">Small HSPs</td>
<td>HspB1, alpha-B crystallin</td>
</tr>
<tr>
<td class="label">Component</td>
<td>Genes</td>
</tr>
<tr>
<td class="label">E1 ubiquitin-activating</td>
<td>UBA1, UBA2</td>
</tr>
<tr>
<td class="label">E2 ubiquitin-conjugating</td>
<td>Multiple</td>
</tr>
<tr>
<td class="label">E3 ubiquitin-ligases</td>
<td>PARKIN, FBXO7</td>
</tr>
<tr>
<td class="label">Deubiquitinases</td>
<td>Multiple</td>
</tr>
</table>

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. [@protein2023]

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. [@amyloid2022]

--- [@tau2023]

Amyloid and APP Family

Amyloid Precursor Protein Family

Significance

The APP family is central to AD pathogenesis. APP is cleaved by BACE1 and [gamma-secretase](/entities/gamma-secretase) to produce [amyloid-beta](/proteins/amyloid-beta). APLP proteins have overlapping functions but do not produce amyloid-beta, suggesting functional redundancy that could be therapeutically exploited.

Tau Protein Family

MAPT Gene Family

Tauopathies

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

Synuclein Family

Alpha-Synuclein Family

Therapeutic Implications

Beta-synuclein may protect against alpha-synuclein aggregation, suggesting that enhancing beta-synuclein or blocking gamma-synuclein could be therapeutic strategies.

Apolipoprotein Family

APOE and Related Proteins

APOE Isoforms

• APOE ε2: Protective, associated with longevity
• APOE ε3: Most common, neutral risk
• APOE ε4: Major risk factor, ~40% of AD patients

Glutamate Receptor Families

Ionotropic Glutamate Receptors

Metabotropic Glutamate Receptors

Protein Kinase Families

Neurodegeneration-Relevant Kinases

Kinase Inhibitor Considerations

Kinase inhibitors face challenges:

• Broad specificity may cause off-target effects
• Adaptive feedback mechanisms
• [Blood-brain barrier](/entities/blood-brain-barrier) penetration

Protease Families

APP-Processing Proteases

Other Proteases

Protein Quality Control Families

Heat Shock Protein Families

Ubiquitin System

Therapeutic Target Clusters

Cluster 1: Protein Aggregation

• Amyloid family
• Tau family
• Synuclein family

Cluster 2: Neuroinflammation

• [Complement system](/entities/complement-system)
• TLR signaling
• Cytokine receptors

Cluster 3: Synaptic Function

• Glutamate receptors
• Synaptic proteins
• Ion channels

Cluster 4: Cellular Quality Control

• [Autophagy](/entities/autophagy) proteins
• Ubiquitin system
• [Heat shock proteins](/entities/heat-shock-proteins)

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References