PINK1 — PTEN Induced Kinase 1

PINK1 — PTEN Induced Kinase 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PINK1 — PTEN Induced Kinase 1</th>
</tr>
<tr> [@phosphorylation2014]
<td class="label">Symbol</td> [@characterization2010]
<td><strong>PINK1</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>PTEN Induced Kinase 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>1p36.12</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/65018" target="_blank">65018</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000158828" target="_blank">ENSG00000158828</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/608309" target="_blank">608309</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9BXM7" target="_blank">Q9BXM7</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Parkinson's Disease](/diseases/parkinsons-disease)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Substantia nigra, Cerebral cortex, Mitochondria (widespread)</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">Q456X, G309D, W437X, E240K, A168P, L347P, M341I, C-terminal mutations</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</

PINK1 — PTEN Induced Kinase 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PINK1 — PTEN Induced Kinase 1</th>
</tr>
<tr> [@phosphorylation2014]
<td class="label">Symbol</td> [@characterization2010]
<td><strong>PINK1</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>PTEN Induced Kinase 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>1p36.12</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/65018" target="_blank">65018</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000158828" target="_blank">ENSG00000158828</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/608309" target="_blank">608309</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9BXM7" target="_blank">Q9BXM7</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Parkinson's Disease](/diseases/parkinsons-disease)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Substantia nigra, Cerebral cortex, Mitochondria (widespread)</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">Q456X, G309D, W437X, E240K, A168P, L347P, M341I, C-terminal mutations</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2147 edges</a></td>
</tr>
</table>

PINK1 — PTEN Induced Kinase 1

Introduction

Pink1 — Pten Induced Kinase 1 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Pathway / Mechanism Diagram

Overview

PINK1 (PTEN Induced Kinase 1) is a gene located on chromosome 1p36.12 that encodes a serine/threonine-protein kinase crucial for mitochondrial quality control[@hereditary2004]. Pathogenic mutations in PINK1 cause autosomal recessive early-onset Parkinson's Disease, making it one of the most important genes linked to familial PD[@pink2010]. The discovery of PINK1 mutations as a cause of PD in 2004 revealed the critical role of mitochondrial dysfunction in disease pathogenesis.

The protein encoded by PINK1 is [PINK1/proteins), a 581-amino acid kinase that localizes to mitochondria. See the protein page for detailed structural and functional information.

Gene Structure

The PINK1 gene spans approximately 1.5 Mb of genomic DNA on chromosome 1p36.12 and consists of 8 exons[@mitochondrial2012]. The gene produces a single transcript encoding the PINK1 protein kinase.

Regulatory Elements

The PINK1 promoter contains several regulatory elements:

• p53 binding sites: PINK1 is a p53 target gene
• FOXO3a response elements: Regulated by FOXO3a transcription factor
• AMPK response elements: Energy status affects expression
• [NF-κB](/entities/nf-kb) sites: Inflammation can modulate expression

• Transcriptional activation: p53, FOXO3a, and AMPK increase expression
• Post-transcriptional regulation: Various miRNAs target PINK1 mRNA
• Epigenetic modifications: [DNA methylation](/entities/dna-methylation) patterns affect expression

Expression Patterns

In the healthy brain, PINK1 is expressed at high levels in:

• Substantia nigra pars compacta: Dopaminergic [neurons](/entities/neurons)
• Cerebral [cortex](/brain-regions/cortex): Pyramidal neurons
• [Hippocampus](/brain-regions/hippocampus): CA1 and dentate gyrus regions
• Cerebellum: Purkinje cells
• Peripheral tissues: Heart, skeletal muscle, testis

Normal Physiological Function

PINK1 plays several essential roles in mitochondrial biology:

Disease Mechanisms

Parkinson's Disease

PINK1 mutations cause autosomal recessive PD through loss of function[@mitochondrial2006]:

Loss of Kinase Activity

• Reduced or absent kinase activity
• Inability to phosphorylate Parkin and other substrates
• Failure to initiate mitophagy
• Accumulation of damaged mitochondria

Pathogenic Mechanism

Genotype-Phenotype Correlation

• PINK1 mutations cause early-onset PD (mean age 30-50 years)
• Typical phenotype: Tremor-dominant, good levodopa response
• Some patients develop psychiatric symptoms
• Disease progression is generally slower than idiopathic PD

Key Mutations

| Mutation | Type | Effect |
|----------|------|--------|
| Q456X | Nonsense | Truncation, loss of kinase domain |
| W437X | Nonsense | Truncation, loss of kinase domain |
| G309D | Missense | Reduced kinase activity |
| E240K | Missense | Impaired substrate binding |
| A168P | Missense | Destabilized protein |
| L347P | Missense | Reduced activity |
| C-terminal mutations | Various | Impaired mitochondrial targeting |

The PINK1-Parkin Pathway

PINK1 and PRKN (Parkin) work together in mitochondrial quality control[@phosphorylation2014]:

Step 1: Mitochondrial Damage

• Loss of mitochondrial membrane potential
• Import blockade causes PINK1 accumulation

Step 2: PINK1 Activation

• PINK1 accumulates on outer mitochondrial membrane
• Autophosphorylation activates kinase domain

Step 3: Parkin Recruitment

• PINK1 phosphorylates ubiquitin
• Phospho-ubiquitin activates Parkin
• Parkin is recruited to mitochondria

Step 4: Mitophagy

• Parkin ubiquitinates mitochondrial proteins
• [Autophagy](/mechanisms/autophagy-lysosome-neurodegeneration) receptors recognize ubiquitinated mitochondria
• Mitochondria are engulfed and degraded

Therapeutic Approaches

Kinase Activity Restoration

• Kinase activators: Small molecules that enhance PINK1 activity
• Stabilizing mutations: Pharmacological chaperones
• Protein replacement: Recombinant PINK1 delivery

Mitophagy Enhancement

• [mTOR](/entities/mtor) inhibitors: Rapamycin and analogs
• AMPK activators: AICAR, metformin
• Natural compounds: Urolithin A, resveratrol

Mitochondrial Protection

• Antioxidants: CoQ10, MitoQ
• Mitochondrial biogenesis inducers: PGC-1α activators

Animal Models

Several models have been developed:

• PINK1 knockout mice: Show mitochondrial dysfunction but not neurodegeneration
• PINK1 knockdown zebrafish: Display locomotion defects
• Drosophila pink1 mutants: Severe mitochondrial defects and neurodegeneration

Research Directions

Current research focuses on:

• Developing PINK1 kinase activators
• Understanding the full repertoire of PINK1 substrates
• Identifying biomarkers for PINK1-linked PD
• Elucidating the relationship with sporadic PD

See Also

• [PINK1 Protein/proteins)

• [Parkinson's Disease/diseases)

• [Mitophagy Pathway/mechanisms)

Background

The study of Pink1 — Pten Induced Kinase 1 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.

Brain Atlas Resources

• [Allen Human Brain Brain Atlas - PINK1 Expression](https://human.brain-map.org/microarray/search/show?search_term=PINK1)
• [Allen Cell Type Atlas](https://celltypes.brain-map.org/)
• [BrainSpan Transcriptome Atlas](https://brainspan.org/)
• [Allen Mouse Brain Atlas](https://mouse.brain-map.org/)

External Links

• NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/65018](https://www.ncbi.nlm.nih.gov/gene/65018)
• Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000158828](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000158828)
• OMIM: [https://omim.org/entry/608309](https://omim.org/entry/608309)
• UniProt: [https://www.uniprot.org/uniprot/Q9BXM7](https://www.uniprot.org/uniprot/Q9BXM7)
• Allen Human Brain Atlas: [PINK1 expression](https://human.brain-map.org/microarray/search/show?search_term=PINK1)
• PD Gene: [PINK1 at pdgene.org](https://www.pdgene.org/geneinfo/19)

Allen Brain Atlas Data

Gene Expression

• Substantia nigra - Dopaminergic neurons
• Hippocampus - Pyramidal neurons
• Cerebral cortex - Layer 5 neurons
• Heart - High expression (not brain-related)

Single-Cell Expression

• Dopaminergic neurons
• Pyramidal glutamatergic neurons
• Cardiac muscle cells (outside brain)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving PINK1 — PTEN Induced Kinase 1 discovered through SciDEX knowledge graph analysis:

Associated Diseases

• Als — associated with

• ALS — associated with

• Alzheimer — associated with

• Alzheimer disease — associated with

• Alzheimer Disease — associated with

• Alzheimer's disease — associated with

• amyotrophic lateral sclerosis — risk factor for

• Amyotrophic Lateral Sclerosis — causes

• dementia — associated with

• Dementia — associated with

• dementia with Lewy bodies — associated with

• Dementia with Lewy bodies — associated with

• early-onset Parkinson disease — risk factor for

• Early Onset Parkinson's Disease — risk factor for

• frontotemporal — associated with

• Lewy body dementia — implicated in

• Parkinson — associated with

• Parkinson disease — associated with

• Parkinson Disease — risk factor for

• Parkinson's disease — associated with

• Parkinson's Disease — associated with

• Parkinson'S Disease — risk factor for

• PARKINSON'S DISEASE — biomarker for

• PARKINSONS_DISEASE — associated with