Caspase-6 and neurodegeneration

• Published in: Trends in neurosciences (Regular ed.) Vol. 34; no. 12; pp. 646 - 656
• Main Authors: Graham, Rona K, Ehrnhoefer, Dagmar E, Hayden, Michael R
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.12.2011; Elsevier; Elsevier Sequoia S.A
• Subjects: Alzheimer Disease - enzymology; Alzheimer Disease - pathology; Amino acids; Animals; Apoptosis; Biological and medical sciences; Brain; Caspase 6 - chemistry; Caspase 6 - metabolism; Caspase Inhibitors; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Enzyme Activation; Fundamental and applied biological sciences. Psychology; General aspects. Models. Methods; Humans; Huntington Disease - enzymology; Huntington Disease - pathology; Medical sciences; Models, Molecular; Morphology; Nerve Degeneration - enzymology; Nerve Degeneration - pathology; Neurodegeneration; Neurology; Neurosciences; Protein Conformation; Vertebrates: nervous system and sense organs; Nervous system diseases; Alzheimer disease; Huntington disease; Terminal stage; Review; Inactivation; Genetic disease; Cerebral disorder; Morphology; Central nervous system disease; Degenerative disease; Extrapyramidal syndrome; Apoptosis
• ISSN: 0166-2236; 1878-108X
• DOI: 10.1016/j.tins.2011.09.001

Caspases are cysteine-aspartic proteases that post-translationally modify their substrates through cleavage at specific sites, which causes either substrate inactivation or a gain of function through the generation of active fragments. Currently, each caspase is categorized as either an initiator of apoptosis or an end-stage executioner. Caspase-6 was originally identified as an executioner caspase owing to its role in cleavage of nuclear lamins. However, it has since been shown that caspase-6 cleaves caspases-2, 3 and 8. Furthermore, active caspase-6 is present in post mortem brains of Huntington and Alzheimer disease subjects that do not yet display apoptotic morphology, which suggests a function distinct from its well-validated executioner role. In this review, we discuss evidence to date regarding the role of caspase-6 in neurodegeneration. The findings suggest that selective inhibitors of caspase-6 may have therapeutic potential for various neurodegenerative disorders.