Calpains in the Molecular Pathogenesis of Polyglutamine Disorders and Their Potential as a Therapeutic Target

Abstract

Together with cancer and cardiovascular disorders, neurodegenerative diseases such as Alzheimer and Parkinson disease are an increasingly important medical issue for the aging society of the 21st century. Multiple factors such as environmental influences and individual living conditions act as important modulators of neuropathology. Despite various forms of neurodegenerative diseases, many similarities exist in the underlying molecular pathomechanisms. These are thus promising targets for medical interventions. Therefore, research on genetically determined forms featuring a singular trigger allows to understand these common processes and to transfer acquired knowledge to other neurological diseases. In view of this fact, the current work investigates the validity of the toxic fragment hypothesis using the example of two polyglutamine diseases, Huntington disease and spinocerebellar ataxia type 3. This widely-described theory assumes that molecularly processed disease proteins in the form of toxic and aggregation-prone fragments enhance neurodegenerative effects. Amongst others, endogenous enzymes such as caspases and calcium-dependent calpains have been associated with the proteolytic cleavage of the disease-causing proteins, a source for toxic fragments. The present study focused on the analysis of the calpain-mediated fragmentation of the mutant proteins huntingtin and ataxin-3, as well as on the detection of the enzymatic overactivation of calpains in cell and animal models of Huntington disease and spinocerebellar ataxia type 3. The investigations carried out here confirmed the influence of calpains on neurodegenerative processes in both polyglutamine diseases. Moreover, huntingtin and ataxin-3 were found to be cleaved at specific amino acid positions within the protein, and the resulting fragments exhibited both an increased toxicity and aggregation propensity. In addition, direct as well as indirect pharmacological inhibition of calpains and genetic modification of cleavage sites within the disease protein attenuated these processes, yielding positive effects on the respective molecular pathology. Future studies including the extension to other neurodegenerative diseases are necessary to further investigate the general validity of this pathomechanism. In this way, therapeutically applicable and effective strategies against neurodegeneration may be developed.