Druggable Genome Coverage

Druggable Genome Coverage

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">Druggable Genome Coverage</th>
</tr>
<tr>
<td class="label">Category</td>
<td>Genes</td>
</tr>
<tr>
<td class="label">All protein-coding genes</td>
<td>~20,000</td>
</tr>
<tr>
<td class="label">Druggable genes (ChEMBL)</td>
<td>~4,500</td>
</tr>
<tr>
<td class="label">Highly druggable (Phase I+)</td>
<td>~2,000</td>
</tr>
<tr>
<td class="label">Currently targeted by drugs</td>
<td>~600</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">BACE1</td>
<td>BACE1</td>
</tr>
<tr>
<td class="label">[Gamma-secretase](/entities/gamma-secretase)</td>
<td>[PSEN1](/entities/psen1)/2</td>
</tr>
<tr>
<td class="label">Aβ aggregation</td>
<td>[APP](/entities/app-protein)</td>
</tr>
<tr>
<td class="label">Aβ clearance</td>
<td>[APOE](/proteins/apoe)</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">Tau kinases</td>
<td>[GSK3B](/entities/gsk3-beta), [CDK5](/proteins/cdk5)</td>
</tr>
<tr>
<td class="label">Tau acetylation</td>
<td>EP300</td>
</tr>
<tr>
<td class="label">Tau aggregation</td>
<td>[MAPT](/proteins/tau)</td>
</tr>
<tr>
<td class="label">Tau clearance</td>
<td>Macroautophagy</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">Cholinergic</td>
<

Druggable Genome Coverage

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">Druggable Genome Coverage</th>
</tr>
<tr>
<td class="label">Category</td>
<td>Genes</td>
</tr>
<tr>
<td class="label">All protein-coding genes</td>
<td>~20,000</td>
</tr>
<tr>
<td class="label">Druggable genes (ChEMBL)</td>
<td>~4,500</td>
</tr>
<tr>
<td class="label">Highly druggable (Phase I+)</td>
<td>~2,000</td>
</tr>
<tr>
<td class="label">Currently targeted by drugs</td>
<td>~600</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">BACE1</td>
<td>BACE1</td>
</tr>
<tr>
<td class="label">[Gamma-secretase](/entities/gamma-secretase)</td>
<td>[PSEN1](/entities/psen1)/2</td>
</tr>
<tr>
<td class="label">Aβ aggregation</td>
<td>[APP](/entities/app-protein)</td>
</tr>
<tr>
<td class="label">Aβ clearance</td>
<td>[APOE](/proteins/apoe)</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">Tau kinases</td>
<td>[GSK3B](/entities/gsk3-beta), [CDK5](/proteins/cdk5)</td>
</tr>
<tr>
<td class="label">Tau acetylation</td>
<td>EP300</td>
</tr>
<tr>
<td class="label">Tau aggregation</td>
<td>[MAPT](/proteins/tau)</td>
</tr>
<tr>
<td class="label">Tau clearance</td>
<td>Macroautophagy</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">Cholinergic</td>
<td>ACHE, BCHE</td>
</tr>
<tr>
<td class="label">Glutamatergic</td>
<td>NMDA, AMPA</td>
</tr>
<tr>
<td class="label">Serotonergic</td>
<td>HTR1A, HTR2A</td>
</tr>
<tr>
<td class="label">Dopaminergic</td>
<td>DRD1-DRD5</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">[Alpha-synuclein](/proteins/alpha-synuclein)</td>
<td>SNCA</td>
</tr>
<tr>
<td class="label">[GBA](/entities/gba) enzyme</td>
<td>GBA</td>
</tr>
<tr>
<td class="label">LRRK2 kinase</td>
<td>LRRK2</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">D1 receptor</td>
<td>DRD1</td>
</tr>
<tr>
<td class="label">D2 receptor</td>
<td>DRD2</td>
</tr>
<tr>
<td class="label">MAO-B</td>
<td>MAOB</td>
</tr>
<tr>
<td class="label">COMT</td>
<td>COMT</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">Complex I</td>
<td>Multiple</td>
</tr>
<tr>
<td class="label">PINK1</td>
<td>PINK1</td>
</tr>
<tr>
<td class="label">PARKIN</td>
<td>PRKN</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">SOD1</td>
<td>SOD1</td>
</tr>
<tr>
<td class="label">[C9orf72](/entities/c9orf72)</td>
<td>C9orf72</td>
</tr>
<tr>
<td class="label">FUS</td>
<td>FUS</td>
</tr>
<tr>
<td class="label">[TDP-43](/mechanisms/tdp-43-proteinopathy)</td>
<td>TARDBP</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Gene</td>
</tr>
<tr>
<td class="label">NMDA receptor</td>
<td>GRIN1/2</td>
</tr>
<tr>
<td class="label">Antioxidant</td>
<td>NFE2L2</td>
</tr>
<tr>
<td class="label">Anti-apoptotic</td>
<td>BCL2</td>
</tr>
</table>

This page analyzes the coverage of neurodegenerative disease genes within the druggable genome, identifying which disease-relevant genes have known drug targets and where therapeutic development opportunities exist. Understanding druggable genome coverage helps prioritize research efforts and identify unmet therapeutic needs. [@druggable2023]

The druggable genome refers to genes encoding proteins that can be modulated by drugs, typically including receptors, enzymes, ion channels, and transporters. Current estimates suggest approximately 4,000-5,000 genes are druggable, though fewer than 1,000 are currently targeted by approved drugs. [@alzheimers2024]

--- [@parkinsons2023]

Defining the Druggable Genome

Traditional Druggable Categories

G-Protein Coupled Receptors (GPCRs): The largest drug target class, with approximately 800 members. GPCRs modulate neurotransmission and are implicated in neurodegenerative diseases. Example targets include mGluR5 (metabotropic glutamate receptor) for AD and D1/D2 dopamine receptors for PD. [@als2023]

Ion Channels: Voltage-gated and ligand-gated ion channels are validated targets. Examples include calcium channel blockers for stroke prevention and [NMDA receptor](/entities/nmda-receptor) antagonists for ALS.

Enzymes: Kinases, proteases, and other enzymes offer druggable targets. Examples include [BACE1](/entities/bace1) (beta-secretase) for [amyloid-beta](/proteins/amyloid-beta) production and [LRRK2](/entities/lrrk2) kinase for PD.

Nuclear Receptors: Ligand-activated transcription factors regulate gene expression. PPAR agonists have been explored for neuroinflammation in AD.

Genome-Wide Estimates

Alzheimer's Disease Druggable Coverage

Amyloid Pathway Coverage

Tau Pathway Coverage

Neurotransmission Coverage

Assessment

Approximately 35% of AD-relevant genes are in the druggable genome, but coverage varies by pathway. Amyloid and tau targets have lower success rates than neurotransmitter modulation.

Parkinson's Disease Druggable Coverage

Alpha-Synuclein Pathway Coverage

Dopamine Pathway Coverage

Mitochondrial Function Coverage

Assessment

PD shows good coverage of symptomatic targets (dopamine pathway) but limited disease-modifying targets.

ALS Druggable Coverage

Key Target Coverage

Neuroprotection Pathways

Assessment

ALS has limited druggable genome coverage for major genetic targets, explaining the lack of effective disease-modifying therapies.

Gap Analysis

High-Priority Unmet Needs

Emerging Opportunities

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