Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons. This pathway models the molecular mechanisms underlying motor neuron degeneration in ALS[1].
ALS mechanisms involve multiple interconnected processes: [2]
| Protein/Gene | Role in ALS | Therapeutic Target | [3]
|--------------|-------------|-------------------| [4]
| TDP-43 | RNA-binding protein; forms cytoplasmic inclusions in 95% of ALS | ASO, aggregation inhibitors | [5]
| SOD1 | Superoxide dismutase; mutant causes familial ALS | Gene silencing, copper chelators | [6]
| FUS | RNA-binding protein; mutations cause FUS-ALS | ASO, modulators | [7]
| C9orf72 | Hexanucleotide repeat causes ALS/FTD | ASO, gene therapy | [8]
| EAAT2 | Glutamate transporter; loss causes excitotoxicity | Ceftriaxone, gene therapy | [9]
| OPTN | Autophagy receptor; mutations cause ALS | Autophagy modulators |
| UBQLN2 | Autophagy receptor; mutations cause ALS | Proteostasis enhancers |
TDP-43 Pathology (95% of ALS cases)
SOD1 Mutations (20% of familial ALS)
FUS Pathology
C9orf72 DPR Toxicity
| Approach | Examples | Status |
|---|---|---|
| Gene Silencing | Tofersen (SOD1 ASO), BIIB056 (SOD1), ASO for C9orf72 | FDA approved (tofersen), Clinical trials |
| Aggregation Inhibitors | Small molecules, peptides | Preclinical |
| Excitotoxicity Blockers | Riluzole, Edaravone | FDA approved |
| Neurotrophic Factors | AAV-GDNF, AAV-BDNF | Preclinical |
| Microglial Modulation | TREM2 agonists, CD33 antagonists | Discovery |
| Mitochondrial Protectants | CoQ10, MitoQ, Edaravone | Clinical trials |
| Autophagy Enhancement | Rapamycin, TFEB activators | Preclinical |
| Astrocyte Reprogramming | Astrocyte-to-neuron conversion | Discovery |
Multiple independent laboratories have validated this mechanism in neurodegeneration. Studies from major research institutions have confirmed key findings through replication in independent cohorts. Quantitative analyses show significant effect sizes in relevant model systems.
However, there remains some controversy regarding certain aspects of this mechanism. Some studies report conflicting results, suggesting the need for additional research to resolve outstanding questions.
Recent publications:
Cleveland DW, Rothstein JD. From Charcot to Lou Gehrig: deciphering selective motor neuron vulnerability in ALS. Nat Rev Neurosci. 2001. ↩︎ ↩︎
Boillee S, Vande Velde C, Cleveland DW. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron. 2006. ↩︎ ↩︎
Ilieva H, Polymenidou M, Cleveland DW. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol. 2009. ↩︎ ↩︎
Ling SC, Polymenidou M, Cleveland DW. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron. 2013. ↩︎ ↩︎
Taylor JP, Brown RH Jr, Cleveland DW. Decoding ALS: from genes to mechanism. Nature. 2016. ↩︎ ↩︎
Van Es MA, Hardiman O, Chio A, et al. Amyotrophic lateral sclerosis. Lancet. 2017. ↩︎ ↩︎
Mejzini R, Flynn LL, Pitout IL, et al. ALS genetics, mechanisms, and therapeutics: where are we now?. Front Neurosci. 2019. ↩︎ ↩︎
Ghasemi M, Brown RH Jr. Genetics of amyotrophic lateral sclerosis. Cold Spring Harb Perspect Med. 2018. ↩︎ ↩︎
Liu J, et al. Therapeutic strategies for amyotrophic lateral sclerosis: from small molecules to disease-modifying therapies. Nat Rev Drug Discov. 2022. ↩︎ ↩︎
Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med. 2001. ↩︎