Intrinsic Brain Signaling Pathways: Targets of Neuron Degeneration

Abstract

Cancer and neurodegenerative disease are two of the greatest worries facing the aging population. Alteration in cell signaling pathways is a molecular process that underlies many cancers and is the targets of therapies. Recent data indicate that these pathways also have a key role in neurodegenerative disease. Glutamine tract expansion triggers nine neurodegenerative diseases most likely by conferring toxic properties to the mutant protein. Spinocerebellar ataxia type 1 (SCA1) is typically a late-onset fatal autsosomal dominant neurodegenerative disease characterized by loss of motor coordination and balance. A characteristic feature of SCA1 pathology is atrophy and loss of Purkinje cells (PCs) from the cerebellar cortex. In SCA1, phosphorylation of ataxin-1 (ATXN1) at Ser776 is one biochemical feature thought to be key for pathogenesis. We found that replacing Ser776 with a phospho-mimicking Asp amino acid converts ATXN1 with a wild type glutamine tract, ATXN1[30Q]-D776, into a pathogenic protein. Yet, in contrast to disease induced by ATXN1[82Q] that progresses from dysfunction to cell death, ATXN1[30Q]-D776-induced disease failed to progress beyond dysfunction. These results support a disease model where disease initiation and subsequent neuronal dysfunction are distinct from progression to cell death. Ser776, presumably its phosphorylation, is critical for the pathogenic pathway leading to neuronal dysfunction, while an expanded polyglutamine tract is essential for further progression to neuronal death. A cerebellar extract-based phosphorylation assay revealed that S776 phosphorylation is regulated by the kinase PKA and the phosphatase PP2A. These date form the basis of a small molecule inhibitor screen that could provide an effective treatment for SCA1.