GENETIC PATHWAY POTENTIAL
Advances in the genetics, pathology and cell biology underlying chronic neurodegenerative disease have identified pathways that trigger neurodegeneration and contribute to disease onset and progression. Denali is applying deep scientific and drug development expertise to fully harvest the potential of these pathways in order to discover effective molecular therapeutics.
Rapid progress in identifying human genetic risk associated with neurodegenerative disease has revealed numerous genes involved in neurodegeneration. Degenogenes are genes that when mutated cause, or are major risk factors for, neurodegenerative disease. These degenogenes highlight important disease pathways for therapeutic discovery, including lysosomal function, glial biology and cellular homeostasis.
The lysosomal system, the disposal and recycling compartment of the cell, is involved in the digestion and processing of proteins and lipids in brain cells. Dysfunction of the lysosomal system is associated with several neurodegenerative disorders, including Parkinson’s disease and neurodegeneration in the context of lysosomal storage diseases, or LSDs. Therapeutics designed to correct lysosomal dysfunction are a promising approach to treat neurodegeneration.
The human brain contains several types of glial cells. These cells serve various functions in the brain, including supporting neuronal health, pruning neuronal synapses, and providing immune surveillance and response. Genetic and pathological data suggest that glial dysfunction significantly contributes to neurodegenerative disease. Correcting glial dysfunction represents an attractive therapeutic strategy.
Many degenogenes directly alter cellular homeostasis in the brain. Specifically, defects in protein, RNA or metabolic homeostasis leads to the death of neurons and dysfunction of the nervous system. This includes spreading of protein aggregates resulting in proteinopathy in Alzheimer’s and Parkinson’s diseases, and the aggregation of RNA binding proteins disrupting cellular stress response in ALS and Alzheimer’s disease. Therapies that correct defects in cellular homeostasis have the potential to halt neurodegeneration.
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