The role of caspases in AD-associated neurotoxicity (left), and dysregulation of apoptosis in cancer cells (right).

Neurodegenerative Disease

Irregular caspase activation has been associated with several neurodegenerative diseases. Caspase activation is elevated in animal models of amyotrophic lateral sclerosis (ALS), and is detected in spinal cord samples from ALS patients. In Huntington’s disease, caspase activation is associated with early disease stages, and caspase expression increases with disease progression. Huntingtin protein (HTT) can also be directly cleaved by caspases, which further contributes to disease features. Evidence also suggests that caspases can cleave amyloid precursor protein (APP), which is processed into neurotoxic components associated with Alzheimer’s disease (AD). In certain AD models, caspase activation precedes neuronal cell death.

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Cancer

Tumor cells avoid apoptosis by disrupting upstream signaling of caspase pathways. This includes upregulation of anti-apoptotic proteins like Bcl-2, which was originally discovered as an oncogene, and downregulation of pro-apoptotic proteins like Bax. Expression of these apoptotic regulators are controlled by p53, a major tumor suppressor. Tumor cells can also have reduced caspase expression or have loss-of-function caspase mutations. Other methods of apoptosis evasion include decreased expression of Fas and increased expression of decoy Fas receptors that help cancer cells avoid CTL and NK cell-mediated killing.

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Autoimmunity and Inflammation

Decreased apoptosis function can lead to autoimmune disorders. Mutations that lower the function of Fas, FasL, or caspase 10 causes autoimmune lymphoproliferative syndrome (ALPS), which results from the lack of autoreactive T cell death during selection in the thymus. Since caspase 1 activity produces activated IL-1β, caspase 1 has been implicated in a number of inflammatory diseases. Increased IL-1β levels has been associated with type 2 diabetes, gout, and certain types of arthritis.

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References:

• Zhang et al. APP Processing in Alzheimer's Disease. Mol Brain (2011). PMID: 21214928
• Bano et al. Neurodegenerative Processes in Huntington's Disease. Cell Death Dis (2011). PMID: 22071633
• McIlwain et al. Caspase Functions in Cell Death and Disease. Cold Spring Harb Perspect Biol (2013). PMID: 23545416
• Friedlander. Apoptosis and caspases in neurodegenerative diseases. N Engl J Med (2003). PMID: 12672865
• Elmore. Apoptosis: A Review of Programmed Cell Death. Toxicol Pathol (2007). PMID: 17562483
• Portt et al. Anti-apoptosis and cell survival: A review. Biochimica et Biophysica Acta (2011). PMID: 20969895. 

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