SCA1 is an autosomal dominant cerebellar ataxia associated with mutations in the gene encoding the ataxin-1 protein (ATXN1, 87 kDa) and the formation of nuclear inclusions containing ATXN1. Recent studies suggest that understanding the physiological function of ATXN1 is essential to decipher the mechanisms of pathogenesis. We found an alternative translation initiation site in the +3 reading frame of the ATXN1 gene. This alternative initiation site produces a novel 21 kDa protein with an amino acid sequence completely different from that of ATXN1. Remarkably, this new protein that we called AltATXN1 co-localizes and interacts with ATXN1 in nuclear inclusions. In contrast, in the absence of ATXN1, AltATXN1 has a homogeneous nucleoplasmic distribution. AltATXN1 interacts with mRNAs and its nuclear localization is dependent on transcription. Thus, our results demonstrate that the ATXN1 gene is a gene that encodes two different proteins. The role of AltATXN1 in SCA1 remains to be determined.
Prion diseases involve the conversion of the prion protein (PrPC) into a proteinase K resistant isoform (PrPSc). PrPC is a glycoprotein anchored to the plasma membrane by a glycosylphosphatidylinositol anchor. The conversion PrPC -> PrPSc triggers neurotoxic mechanisms involved in these neurodegenerative disorders. The physiological function of PrPC is still unknown. We have re-analyzed the sequence encoding PrPC, and we found an alternative open reading frame overlapping the sequence encoding PrPC. We have shown that the protein encoded by this overlapping open reading frame, termed AltPrP, is co-expressed with PrPC. We demonstrated that AltPrP is a mitochondrial protein inserted into the outer membrane. We are investigating the possibility that AltPrP is linked to the conversion PrPC -> PrPSc and/or neurodegeneration in prion diseases.
Neurodegenerative diseases such as Alzheimer's disease, prion diseases, Parkinson's disease, amyotrophic lateral sclerosis, spinocerebellar ataxia and frontotemporal dementia are a group of disorders characterized by the accumulation in the nervous system of abnormal proteins that are toxic to neurons. Although each disease displays specific clinical manifestations, abnormal proteins may exert their toxicity through common pathways. The project, in collaboration with an international consortium is based on prior identification of mechanisms common to prion diseases and Alzheimer's disease. In diseased neurons, the PDK1 enzyme is overactive and blocks the protective activity of another enzyme, TACE. Inhibition of PDK1 in mouse models of these two diseases prevents toxicity.
By combining in vitro and in vivo approaches and analysis of cells and tissues, this project will test the involvement of the PDK1 / TACE pathway in neurodegenerative diseases mentioned above. Currently there are no effective therapies to delay or stop these deadly diseases. Our work will be to determine whether PDK1 may be a therapeutic target for these fatal diseases.