PL‐03‐02: Dissecting the function of APP by the characterization of APP‐interacting proteins

not available. S3-01-02 TDP-43 PROTEINOPATHIES Ian Mackenzie, Vancouver General Hospital, Vancouver, BC, Canada; University of British Columbia, Vancouver, BC, Canada. Contact e-mail: ian.mackenzie@vch.ca Background: The TAR DNA binding protein TDP-43 is a nuclear protein expressed in various tissues, with functions that include transcription repression and activation of exon skipping. The physiological role of TDP-43 in the brain is currently unknown, however it is normally localized to the nucleus of neurons and some glia. The recent identification of abnormal TDP-43 as the major pathological protein in the most common subtype of frontotemporal lobar degeneration (FTLD with ubiquitinated inclusions, FTLD-U) and in ALS represents a major breakthrough in understanding the pathogenesis and inter-relationship of these conditions. Defining the clinical and pathological spectrum of this new biochemical class of neurodegenerative disease is the focus of ongoing research. Methods: Literature review. Results: Each of the known genetic causes of familial FTLD-U is associated with a characteristic pattern of neuropathology and in most (including mutations in PGRN, VCP and linked to chromosome 9p) the pathology is TDP-43-positive. The one exception is FTD linked to chromosome 3, caused by a CHMP2B mutation, which has neuronal inclusions that are ubiquitinated but not reactive for TDP-43. The vast majority of sporadic FTLD-U cases also have TDP-43 pathology, however there exists a small proportion that are TDP-43-negative. These cases of “atypical” FTLD-U have a highly consistent clinical phenotype, unique neuropathology and probably represent a discrete entity. In ALS, all sporadic and familial cases without SOD1 mutations have TDP-43-positive inclusions in both motor neurons and glia; however, cases with SOD1 mutations have no evidence of pathological TDP-43. An important recent development has been the identification of TDP-43 mutations in some familial ALS. TDP-43 pathology may also coexist in a variety of other neurodegenerative conditions, including hippocampal sclerosis, ALS-parkinsonism-dementia complex of Guam, Pick’s disease and a significant proportion of Alzheimer’s and Lewy body disease. The specific role of TDP-43 in neurodegeneration remains speculative, however, possibilities include loss of some essential nuclear function or disruption of crucial intracellular processes by the accumulation of insoluble, mis-folded protein. Conclusions: The TDP-43 proteinopathies represent an important new class of neurodegenerative disease. Defining the biochemical basis of these conditions will facilitate the development of useful biomarkers and therapies. S3-01-03 PRION THERAPY: TETRACYCLIC COMPOUNDS IN ANIMAL MODELS AND PATIENTS WITH CREUTZFELDT-JAKOB DISEASE Fabrizio Tagliavini, Instituto Nazionale Neurologico, Milano, Italy. Contact e-mail: ftagliavini@istituto-besta.it Background: The prion diseases are fatal neurodegenerative disorders for which no effective treatment is available. A large number of molecules T149 Symposia S3-01: Other Dementias