Applying specialized expertise and deep knowledge of lysosomal biology to treat neurodegenerative diseases.
A New Frontier in Neurodegeneration
New and evolving understanding of the underlying biology of neurodegenerative disease is revealing novel opportunities for therapeutic intervention – lighting the path for therapies with the potential to improve the health of cells in the brain, delaying disease progression and even the onset of symptoms.A Potential for Real Impact
Healthy lysosome function is critical for cellular recycling, homeostasis, and maintaining normal neuronal function. Across multiple nervous system cell types, lysosomal dysfunction can lead to substrate and protein accumulation, inflammation, and cellular damage that contributes to neurodegenerative disease.
Understanding the Underlying Biology
Lysosomes are intricate organelles in cells that play a central role in maintaining cellular health, especially in the cells of the central nervous system. Lysosomal function and the resulting disruption of protein homeostasis has been linked to the development and progression of a range of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a fatal, aggressive form of dementia associated with changes in personality, behavior and language.
A subset of people with FTD have an inherited form of disease caused by mutations in the GRN gene, which codes for the protein progranulin. Progranulin is a protein known to play a key role in lysosomal function and innate immunity in the brain. Progranulin is targeted to lysosomes where it is processed into its biologically active subunits, granulins, which are responsible for maintaining normal lysosomal function. Patients with an FTD-GRN mutation in one allele fail to produce sufficient progranulin, impacting the production of granulins in neuronal lysosomes, triggering progressive neuronal deterioration and eventually death.
Our team has discovered new and evolving insights about the importance of progranulin and granulins in regulating lysosomal health in frontotemporal dementia and is driving the discovery of exciting new medicines for FTD-GRN and other neurodegenerative diseases.
Progranulin is a protein made by various cells in the body, including the cells of the central nervous system. Inside the lysosome, progranulin is processed into granulins, which are key to maintaining protein homeostasis in the cell.
Once thought of as simple cellular waste disposal systems, lysosomes are now understood to be sophisticated, intricate organelles that are central to coordinating our cells’ responses against environmental cues and stress, especially in the cells of the CNS. Arkuda’s primary focus is to utilize these recent insights in lysosomal regulation and biology to develop novel drugs to treat neurodegenerative disorders.
Chris Holler, PhD