Neuropathology of Beta-propeller protein associated neurodegeneration (BPAN): a new tauopathy

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Abstract

Introduction

Beta-propeller protein associated neurodegeneration (BPAN) is associated with mutations in the WD repeat domain 45 ( WDR45) gene on chromosome Xp11 resulting in reduced autophagic flux. This study describes the clinical and neuropathological features of a female 51 year old BPAN case. The clinical history includes learning disability and progressive gait abnormalities since childhood followed by progressive dystonic features in young adulthood. Brain imaging revealed generalised brain atrophy and bilateral mineralisation of the globus pallidus and substantia nigra.

Results

The major pathological findings were observed in the substantia nigra with excess iron deposition, gliosis, axonal swellings and severe neuronal loss. Iron deposition was also observed in the globus pallidus. There was extensive hyperphosphorylated-tau deposition in the form of neurofibrillary tangles, pre-tangles and neuropil threads. Furthermore, histological studies and immunoblotting confirmed a mixed Alzheimer type 3-and 4-repeat tau pathology. Microtubule-associated protein 1A/1B-light chain 3 (LC3) immunoblotting of brain homogenates indicated autophagic activity and may support the role of WDR45 in autophagy.

Conclusions

The widespread Alzheimer-type tau pathology in this disease indicates that this should be considered as a tauopathy and adds further support to the proposal that impaired autophagy may have a role in tauopathies.

Electronic supplementary material

The online version of this article (doi:10.1186/s40478-015-0221-3) contains supplementary material, which is available to authorized users.

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Most cited references 17

Record: found
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Network organization of the human autophagy system

Christian Behrends, Mathew Sowa, Steven P. Gygi … (2010)

Autophagy, the process by which proteins and organelles are sequestered in autophagosomal vesicles and delivered to the lysosome/vacuole for degradation, provides a primary route for turnover of stable and defective cellular proteins. Defects in this system are linked with numerous human diseases. While conserved protein kinase, lipid kinase, and ubiquitin-like (UBL) protein conjugation sub-networks controlling autophagosome formation and cargo recruitment have been defined, our understanding of the global organization of this system is limited. Here, we report a proteomic analysis of the autophagy interaction network (AIN) in human cells under conditions of ongoing (basal) autophagy, revealing a network of 751 interactions among 4 09 candidate interacting proteins with extensive connectivity among sub-networks. Many new AIN components have roles in vesicle trafficking, protein or lipid phosphorylation, and protein ubiquitination, and affect autophagosome number or flux when depleted by RNAi. The six ATG8 orthologs in humans (MAP1LC3/GABARAP proteins) interact with a cohort of 67 proteins, with extensive binding partner overlap between family members, and frequent involvement of a conserved surface on ATG8 proteins known to interact with LC3-interacting regions (LIR) in partner proteins. These studies provide a global view of the mammalian autophagy interaction landscape and a resource for mechanistic analysis of this critical protein homeostasis pathway.

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De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood.

Hirotomo Saitsu, Taki Nishimura, Kazuhiro Muramatsu … (2013)

Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is a recently established subtype of neurodegeneration with brain iron accumulation (NBIA). By exome sequencing, we found de novo heterozygous mutations in WDR45 at Xp11.23 in two individuals with SENDA, and three additional WDR45 mutations were identified in three other subjects by Sanger sequencing. Using lymphoblastoid cell lines (LCLs) derived from the subjects, aberrant splicing was confirmed in two, and protein expression was observed to be severely impaired in all five. WDR45 encodes WD-repeat domain 45 (WDR45). WDR45 (also known as WIPI4) is one of the four mammalian homologs of yeast Atg18, which has an important role in autophagy. Lower autophagic activity and accumulation of aberrant early autophagic structures were demonstrated in the LCLs of the affected subjects. These findings provide direct evidence that an autophagy defect is indeed associated with a neurodegenerative disorder in humans.

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Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms.

Terence Crowther, Michel Goedert, M Spillantini … (1991)

Preparations of dispersed paired helical filaments (PHFs) from the brains of Alzheimer's disease and Down's syndrome patients display on gels three principal bands corresponding to abnormally modified forms of the microtubule-associated protein tau. Interpretation of the pattern is difficult because there are six tau isoforms in normal brain and phosphorylation changes their mobility. By enzymatic dephosphorylation at high temperature, we have shifted the three abnormal bands obtained from dispersed PHFs to align with the six nonphosphorylated tau isoforms. By using antibodies specific for some of the inserts that distinguish the various isoforms and label PHFs, we have established a correspondence between PHFs, abnormal bands, and isoforms. This identification of isoforms is a necessary step in unravelling the molecular pathogenesis of PHFs.

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Author and article information

Contributors

H. Houlden: h.houlden@ucl.ac.uk

Journal

Journal ID (nlm-ta): Acta Neuropathol Commun

Journal ID (iso-abbrev): Acta Neuropathol Commun

Title: Acta Neuropathologica Communications

Publisher: BioMed Central (London )

ISSN (Electronic): 2051-5960

Publication date (Electronic): 30 June 2015

Publication date PMC-release: 30 June 2015

Publication date Collection: 2015

Volume: 3

Electronic Location Identifier: 39

Affiliations

[ ]Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK

[ ]Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK

[ ]Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, London, UK

Article

Publisher ID: 221

DOI: 10.1186/s40478-015-0221-3

PMC ID: 4486689

PubMed ID: 26123052

SO-VID: 73fee8d9-839a-41ca-9477-7f81d697d6ad

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.