eprintid: 3442 rev_number: 5 eprint_status: archive userid: 6 dir: disk0/00/00/34/42 datestamp: 2016-04-13 09:21:47 lastmod: 2016-04-13 09:21:47 status_changed: 2016-04-13 09:21:47 type: article metadata_visibility: show creators_name: Murrell, Jill R. creators_name: Spillantini, Maria Grazia creators_name: Zolo, Paolo creators_name: Guazzelli, Mario creators_name: Smith, Michael J. creators_name: Hasegawa, Masato creators_name: Redi, Francesco creators_name: Crowther, R. Anthony creators_name: Pietrini, Pietro creators_name: Ghetti, Bernardino creators_name: Goedert, Michel creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: creators_id: pietro.pietrini@imtlucca.it creators_id: creators_id: title: Tau Gene Mutation G389R Causes a Tauopathy with Abundant Pick Body-like Inclusions and Axonal Deposits ispublished: pub subjects: RC0321 divisions: CSA full_text_status: none keywords: Axonal tau deposits; Brain metabolism; Frontotemporal dementia; Pick body-like inclusions; Tauopathy abstract: Exonic and intronic mutations in Tau cause familial neurodegenerative syndromes characterized by frontotemporal dementia and dysfunction of multiple cortical and subcortical circuits. Here we describe a G389R mutation in exon 13 of Tau. When 38 years old, the proband presented with progressive aphasia and memory disturbance, followed by apathy, indifference, and hyperphagia. Repeated magnetic resonance imaging showed the dramatic progression of cerebral atrophy. Positron emission tomography revealed marked glucose hypometabolism that was most severe in left frontal, temporal, and parietal cortical regions. Rigidity, pyramidal signs and profound dementia progressed until death at 43 years of age. A paternal uncle, who had died at 43 years of age, had presented with similar symptoms. The proband's brain showed numerous tau-immunoreactive Pick body-like inclusions in the neocortex and the fascia dentata of the hippocampus. In addition, large numbers of tau-positive filamentous inclusions were present in axons in the frontal, temporal, and parietal lobes. Immunoblot analysis of sarkosyl-insoluble tau showed 2 major bands of 60 and 64 kDa. Upon dephosphorylation, these bands resolved into 4 bands consisting of three- and four-repeat tau isoforms. Most isolated tau filaments were straight and resembled filaments found in Alzheimer disease and some frontotemporal dementias with tau mutations. A smaller number of twisted filaments was also observed. Biochemically, recombinant tau proteins with the G389R mutation showed a reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation. Taken together, the present findings indicate that the G389R mutation in Tau can cause a dementing condition that closely resembles Pick's disease. date: 1999 publication: Journal of Neuropathology and Experimental Neurology volume: 58 number: 12 publisher: The Oxford University Press pagerange: 1207-1226 id_number: doi:10.1097/00005072-199912000-00002 refereed: TRUE issn: 0022-3069 official_url: http://doi.org/10.1097/00005072-199912000-00002 citation: Murrell, Jill R. and Spillantini, Maria Grazia and Zolo, Paolo and Guazzelli, Mario and Smith, Michael J. and Hasegawa, Masato and Redi, Francesco and Crowther, R. Anthony and Pietrini, Pietro and Ghetti, Bernardino and Goedert, Michel Tau Gene Mutation G389R Causes a Tauopathy with Abundant Pick Body-like Inclusions and Axonal Deposits. Journal of Neuropathology and Experimental Neurology, 58 (12). pp. 1207-1226. ISSN 0022-3069 (1999)