title: Frontotemporal lobar degeneration with ubiquitinated tau-negative inclusions and additional alpha-synuclein pathology but also unusual cerebellar ubiquitinated p62-positive, TDP-43-negative inclusions.
abstract: Mutations in the progranulin (PGRN) gene on chromosome 17 have been shown to be responsible for one non-tauopathy subtype of familial frontotemporal lobar degeneration - frontotemporal lobar degeneration with ubiquitinated, tau-negative inclusions (FTLD-U). Such cases have pathological similarities to sporadic cases with neuronal inclusions positive for ubiquitin, the ubiquitin binding protein, p62 and the newly recognised protein TDP-43 but negative for hyperphosphorylated (HP) tau. There has been a recent report on two families with a novel progranulin mutation where the neuropathology showed not only TDP-43 neuronal positivity but separate tau and/or alpha-synuclein pathology. We describe an unusual case with some family history but no mutation in the progranulin gene. The pathological features were typical for FTLD-U but with additional significant alpha-synuclein pathology, and unusual ubiquitin-positive, p62-positive, TDP-43-negative inclusions in the cerebellum. This case may represent a further pathological phenotype for familial FTLD-U. It also highlights the need for further investigations on the ubiquitin binding protein p62 as a marker in FTLD-U. It is certainly possible that the presence or absence of these ubiquitinated p62-positive yet TDP-43-negative cerebellar inclusions may act as a useful correlative factor in the future.
authors: Department of Clinical Neuropathology, King's College Hospital, London, UK. andrew.king@kch.nhs.uk
authors: Andrew
authors: A
authors: King
authors: Safa
authors: S
authors: Al-Sarraj
authors: Christopher
authors: C
authors: Shaw
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000378:metabolism*; D000368:Aged; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000032:analysis; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry / Q000473:pathology*; D008297:Male; D000071456:Sequestosome-1 Protein; D054875:Ubiquitination; D051844:alpha-Synuclein / Q000032:analysis*; D016875:tau Proteins / Q000032:analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D051844:alpha-Synuclein; D016875:tau Proteins