Genetic Basis of ALS
Amyotrophic lateral sclerosis is characterized by progressive degeneration of upper and lower motor neurons, leading to muscle weakness, paralysis, and death typically within 3 to 5 years of diagnosis. While most cases are sporadic, approximately 10% are familial with identifiable genetic causes.
Major ALS Genes
SOD1 (Superoxide Dismutase 1)
The first ALS gene identified, with over 180 known mutations. SOD1 mutations cause disease through toxic gain of function rather than loss of enzyme activity. The G93A mutation is the most commonly studied in mouse models.
TARDBP (TDP43)
TDP43 pathology is present in approximately 97% of ALS cases, making it a central player in disease pathogenesis. Mutations cause both familial ALS and frontotemporal dementia.
FUS (Fused in Sarcoma)
Like TDP43, FUS is an RNA binding protein whose mutations cause ALS and FTD. FUS mutations lead to cytoplasmic aggregation and nuclear depletion.
C9orf72
Hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of both ALS and FTD. Disease mechanisms include loss of C9orf72 function, toxic RNA foci, and dipeptide repeat protein toxicity.
Additional ALS Genes
SOD1 Models
SOD1 transgenic mice remain the most widely used ALS models, enabling therapeutic testing and mechanistic studies of motor neuron degeneration.
| Model Type | Features | Applications |
|---|---|---|
| SOD1 G93A Transgenic | High copy number, aggressive disease | Paralysis onset ~90 days, therapeutic testing |
| SOD1 G85R | Alternative mutation, slower progression | Longer therapeutic window studies |
| SOD1 Knockin | Physiological expression levels | Avoids overexpression artifacts |
| SOD1 Knockout | Null allele | Age dependent motor neuron loss studies |
TDP43 Models
TDP43 models address the most common ALS pathology, with TDP43 mislocalization from nucleus to cytoplasm being a pathological hallmark.
| Model Type | Features | Applications |
|---|---|---|
| TDP43 A315T Knockin | Patient derived mutation, endogenous control | Disease modeling without overexpression |
| TDP43 Q331K Knockin | Age dependent motor phenotypes | Progressive TDP43 pathology |
| Conditional TDP43 | Cre dependent expression or deletion | Cell type specific studies |
| TDP43 Knockout | Conditional in motor neurons | Progressive motor phenotypes |
Cell Type Specific Approaches
ALS involves both motor neurons and surrounding glia. Cell type specific gene manipulation reveals distinct contributions to disease.
Motor Neuron Specific
ChAT Cre or VAChT Cre
Reveals cell autonomous disease mechanisms
Astrocyte Specific
GFAP Cre or Aldh1l1 Cre
Demonstrates non cell autonomous toxicity
Microglial Specific
CX3CR1 Cre
Studies microglial contribution to disease progression
Oligodendrocyte Specific
Mog Cre or CNP Cre
Investigates oligodendrocyte dysfunction
Phenotyping ALS Models
Motor Function Assessment
Rotarod
Motor coordination and balance. Decline in latency to fall correlates with disease progression.
Grip Strength
Forelimb and hindlimb grip strength measurement provides quantitative muscle function assessment.
Gait Analysis
Stride length, cadence, and stance time reveal motor deficits before paralysis onset.
Hanging Wire
Neuromuscular function assessment. Time to fall from inverted grid.
Neuropathology Endpoints
- Motor neuron counts: Stereological quantification of ChAT positive neurons in spinal cord ventral horn
- Neuromuscular junction analysis: Innervation status of neuromuscular junctions in hindlimb muscles
- Protein aggregation: Immunohistochemistry for mislocalized TDP43, SOD1 aggregates, or dipeptide repeat proteins
- Gliosis: Astrocyte (GFAP) and microglial (Iba1) activation in spinal cord
Selected Publications in ALS Research
Recent publications demonstrate the utility of genetically engineered mouse models in ALS research:
Ionescu A et al. (2025).
Muscle derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models. ↗Nature Neuroscience 28(4): 821-833
Clausen BE et al. (1999).
Conditional gene targeting in macrophages and granulocytes using LysMcre mice. ↗Transgenic Research 8(4): 265-277
What Researchers Say
“ingenious Targeting Laboratory is highly recommended for generating custom animal models. Past 2 years, we have made 2 conditional knockout mouse lines. All processes of each project were scientifically and professionally handled. Their scientific consulting to initiate the project was superb compared to other companies, and transparency of the project progress reported by project managers was excellent. Their excellency and dedication to meet our needs in a timely manner are invaluable to continuation of our research progress.”
— Hyekyung Plumley, PhD
Warren Center for Neuroscience Drug Discovery
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