Insulin Like Growth Factor 1 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
| Protein Name | Insulin-Like Growth Factor 1 |
|---|
| Gene | IGF1 |
|---|
| UniProt ID | P05019 |
|---|
| Molecular Weight | 7.6 kDa (mature peptide) |
|---|
| Subcellular Localization | Extracellular, Cell Surface |
|---|
| Protein Family | Insulin-like growth factor family |
|---|
| Associated Diseases | Alzheimer's Disease, Parkinson's Disease, ALS, Laron Syndrome, Growth Hormone Insensitivity |
|---|
Insulin-Like Growth Factor 1 (IGF1) is a 70-amino acid peptide hormone that plays crucial roles in growth, development, and cellular survival. In the brain, IGF1 acts as a potent neurotrophic factor promoting neuronal survival, synaptic plasticity, neurogenesis, and myelination. IGF1 is essential for normal brain development and continues to provide neuroprotective effects throughout life.
IGF1 is a single-chain polypeptide with approximately 50% sequence homology to insulin. The protein contains four domains:
- B Domain (residues 1-25): Core binding region
- C Domain (residues 26-33): Connecting peptide (cleaved in mature form)
- A Domain (residues 42-62): Receptor binding region
- D Domain (residues 63-70): C-terminal extension
The mature IGF1 peptide is produced by proteolytic processing from a 154-amino acid preproprotein. Alternative splicing produces different isoforms with varying biological activities.
IGF1 exerts multiple protective and restorative effects on neurons:
- Neuronal Survival: Activates pro-survival signaling through PI3K/Akt and MAPK/ERK pathways
- Synaptic Plasticity: Enhances long-term potentiation (LTP) and memory formation
- Neurogenesis: Promotes proliferation and differentiation of neural stem cells in the subventricular zone and hippocampus
- Myelination: Stimulates oligodendrocyte proliferation and myelin production
- Anti-inflammatory Effects: Modulates microglial activity and reduces neuroinflammation
- Antioxidant Properties: Enhances cellular defense against oxidative stress
Beyond the CNS, IGF1 regulates:
- Linear growth (GH-dependent)
- Muscle mass maintenance
- Bone metabolism
- Cardiac function
- Glucose homeostasis
IGF1 signaling is significantly altered in AD:
- Reduced CSF IGF1: Levels are decreased in AD patients, correlating with cognitive decline
- Impaired Signaling: Post-receptor signaling defects reduce downstream neuroprotective effects
- Amyloid Interaction: Aβ oligomers interfere with IGF1 receptor function
- Tau Pathology: Hyperphosphorylated tau disrupts IGF1 signaling cascades
- Therapeutic Potential: IGF1 administration improves cognitive function in AD mouse models
IGF1 provides neuroprotection for dopaminergic neurons:
- Dopaminergic Protection: IGF1 protects substantia nigra neurons from 6-OHDA and MPTP toxicity
- α-Synuclein Modulation: May reduce α-synuclein aggregation
- Mitochondrial Function: Enhances mitochondrial biogenesis and function
- Clinical Trials: Recombinant IGF1 (Ibutamoren) has been tested in PD patients
IGF1 has been investigated extensively in ALS:
- Motor Neuron Protection: Promotes survival of upper and lower motor neurons
- Neuroprotective Signaling: Activates Akt pathway critical for neuronal survival
- Clinical Trials: Intrathecal IGF1 showed mixed results in ALS trials
- Gene Therapy: AAV-mediated IGF1 delivery approaches are under development
- Huntington's Disease: IGF1 improves motor function and reduces mutant huntingtin toxicity
- Multiple Sclerosis: Promotes remyelination and reduces demyelination
- Peripheral Neuropathy: IGF1 gene therapy shows promise for diabetic neuropathy
IGF1 binding to IGF1R activates:
- Receptor autophosphorylation
- IRS-1/2 recruitment and phosphorylation
- PI3K activation
- Akt phosphorylation and activation
- downstream effects including:
- Bad phosphorylation (anti-apoptotic)
- mTORC1 activation (protein synthesis)
- GSK-3β inhibition (neuroprotection)
- CREB activation (gene transcription)
Alternative signaling cascade:
- Shc adapter protein recruitment
- Grb2/Sos complex binding
- Ras activation
- Raf-MEK-ERK cascade
- Transcription factor activation
- Mecasermin (Increlex): FDA-approved for GH insensitivity
- Ibutamoren (MK-677): Oral GH secretagogue
- Delivery Challenges: Blood-brain barrier penetration issues
- AAV-mediated IGF1 delivery to CNS
- Targeted neuronal expression
- Viral vector approaches in clinical trials
- IGF1R agonists under development
- BBB-penetrant compounds
- Combination approaches
IGF1 levels serve as biomarkers:
- Serum IGF1: Reflects GH-IGF1 axis function
- CSF IGF1: CNS-specific marker (reduced in AD/PD)
- Therapeutic Monitoring: Used to titrate treatment doses
- IGF1 null mice: Severe growth deficiency, neurological deficits
- Neuron-specific knockout: Learning and memory impairments
- IGF1 overexpression: Enhanced neurogenesis, improved cognition
- AAV-IGF1 delivery: Protects against various neurotoxins
The study of Insulin Like Growth Factor 1 Protein 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.
- Bondy CA, et al. (1992). IGF-1 in the brain: a neurotrophic factor. Mol Neurobiol. 6:337-351. PMID:1282667
- Wrigley S, et al. (2017). IGF-1 and neurodegeneration. Adv Exp Med Biol. 1000:59-88. PMID:29218582
- Russo VC, et al. (2009). IGF-1 receptor and neurodegeneration. Cell Mol Life Sci. 66:3402-3424. PMID:19544455
- Carro E, et al. (2002). Circulating insulin-like growth factor I and function. Proc Natl Acad Sci. 99:10185-10190. PMID:12119393
- Torres-Aleman I (2010). Toward a comprehensive therapy for neuroprotection. J Mol Neurosci. 40:111-123. PMID:19690987
- Piriz J, et al. (2011). GH and IGF1 as biomarkers. J Mol Neurosci. 45:158-165. PMID:21327727
- Flood L, et al. (2022). IGF1 therapy in neurodegenerative diseases. Neurobiol Dis. 168:105726. PMID:35278563
- D'Ercole AJ, et al. (1996). IGFs and the brain. Dev Neurosci. 18:1-21. PMID:8840074