SHANK1 — SH3 and Multiple Ankyrin Repeat Domains 3

SHANK1 — SH3 and Multiple Ankyrin Repeat Domains 3

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SHANK1 — SH3 and Multiple Ankyrin Repeat Domains 3</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>SHANK1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>SH3 and Multiple Ankyrin Repeat Domains 3</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19q13.33</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>50856</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>603384</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000161681</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y3I0</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Drug/Approach</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>AAV-Shank1/2/3</td>
</tr>
<tr>
<td class="label">Small molecule</td>
<td>Spine plasticity enhancers</td>
</tr>
<tr>
<td class="label">Peptide</td>
<td>PSD scaffolds</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Shank1 — Sh3 And Multiple Ankyrin Repeat Domains 3 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

SHANK1 — SH3 and Multiple Ankyrin Repeat Domains 3

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SHANK1 — SH3 and Multiple Ankyrin Repeat Domains 3</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>SHANK1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>SH3 and Multiple Ankyrin Repeat Domains 3</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19q13.33</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>50856</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>603384</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000161681</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9Y3I0</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Drug/Approach</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>AAV-Shank1/2/3</td>
</tr>
<tr>
<td class="label">Small molecule</td>
<td>Spine plasticity enhancers</td>
</tr>
<tr>
<td class="label">Peptide</td>
<td>PSD scaffolds</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Shank1 — Sh3 And Multiple Ankyrin Repeat Domains 3 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

SHANK1 encodes a scaffold protein that organizes the postsynaptic density of excitatory synapses. Shank proteins (SHANK1-3) are crucial for synaptic structure, function, and plasticity, linking glutamate receptors to the actin cytoskeleton. [@ref1999]

Gene Information

Normal Function

Shank1 is a postsynaptic scaffold protein that:

• Organizes PSD: Forms the core of the postsynaptic density
• Links receptors to cytoskeleton: Connects AMPA/NMDA receptors to actin
• Regulates spine morphology: Controls dendritic spine shape and size
• Synaptic plasticity: Essential for [LTP](/mechanisms/long-term-potentiation) and LTD
• Signaling pathways: Scaffold for various synaptic signaling molecules

Disease Associations

Alzheimer's Disease

• Role: Synaptic loss and dendritic spine dysfunction
• Mechanism: [Aβ](/proteins/amyloid-beta) oligomers disrupt Shank1 interactions
• Research: Reduced Shank1 in AD brain correlates with cognitive decline

Parkinson's Disease

• Role: Dysfunction in dopaminergic synapse structure
• Mechanism: May affect excitatory/inhibitory balance

Autism Spectrum Disorder

• Role: Synaptic dysfunction
• Mechanism: SHANK1 mutations associated with ASD
• Inheritance: Autosomal dominant and de novo

Schizophrenia

• Role: Synaptic pathology
• Mechanism: Altered Shank1 expression in schizophrenia brain

Expression Pattern

Brain-specific expression:

• [Cortex](/brain-regions/cortex) (layers II-III, V)
• [Hippocampus](/brain-regions/hippocampus) (CA1, CA3)
• Cerebellum (Purkinje cells)
• [Striatum](/brain-regions/striatum)

Therapeutic Targeting

Expression Pattern

The SHANK1 gene exhibits brain-specific expression with highest levels in the cerebral cortex, hippocampus, and olfactory bulb. Within [neurons](/entities/neurons), SHANK1 mRNA is localized to dendrites, where local translation occurs in response to synaptic activity. The protein is enriched in the postsynaptic density of excitatory synapses on dendritic spine heads. Expression is developmentally regulated, with low levels during embryogenesis and a sharp increase during the first three postnatal weeks in mice, coinciding with synaptogenesis and spine maturation. In human brain, SHANK1 is expressed in pyramidal neurons throughout the cortex, with particularly high levels in layer 5 projection neurons that undergo early degeneration in Alzheimer's disease.

Molecular Mechanisms

SHANK1 encodes a 2160-amino acid scaffold protein that serves as a mega-scaffold at excitatory synapses:

• ANK repeat domains (7 repeats): Bind to α-fodrin and other cytoskeletal proteins
• PDZ domain: Binds to PSD-95 and other MAGUK proteins
• Proline-rich region: Interacts with cortactin (actin dynamics) and Homer (metabotropic glutamate signaling)
• SAM domain (C-terminus): Mediates higher-order oligomerization

Research Directions

Current SHANK1 research focuses on:

• How [Aβ](/proteins/amyloid-beta) disrupts SHANK1-actin coupling in AD models
• SHANK1 haploinsufficiency in autism spectrum disorders
• AAV-mediated SHANK1 gene therapy for synaptic restoration
• Small molecules that enhance SHANK1 spine recruitment
• Post-translational modifications in disease states (phosphorylation, sumoylation)
• iPSC models from ASD patients with SHANK1 mutations

Background

The study of Shank1 — Sh3 And Multiple Ankyrin Repeat Domains 3 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

Key Publications

• PSD-95- Synaptic Dysfunction
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• Autism Spectrum Disorders
• SHANK3

External Links

• [NCBI Gene: SHAN- [UniProt: SHANK1](https://www.uniprot.org/uniprot/Q9Y3I0)
• [HGNC: SHANK1](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:29436)

References