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Differential recruitment of UBQLN2 to nuclear inclusions in the polyglutamine diseases HD and SCA3.

ABSTRACT: Accumulation of mutant polyglutamine proteins in intraneuronal inclusions is a hallmark of polyglutamine diseases. Impairment of protein clearance systems and sequestration of clearance-related proteins into inclusions occur in many protein folding diseases, including polyglutamine diseases. The ubiquitin-binding and proteasome adaptor protein UBQLN2 participates in protein homeostasis and localizes to inclusions in various neurodegenerative diseases. Employing mouse models and human brain tissue of Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3), we show that UBQLN2 is selectively recruited to inclusions in HD but not SCA3. Consistent with this result, in a cell-based system mutant HTT interacts with UBQLN2 through the UBA domain while the SCA3 disease protein ATXN3, a deubiquitinating enzyme, does not interact with UBQLN2. Differential recruitment of UBQLN2 to aggregates in HD and SCA3 underscores the heterogeneity of inclusions in polyglutamine diseases and suggests that components of neuronal protein quality control may be differentially perturbed in distinct polyQ diseases.

SUBMITTER: Zeng L

PROVIDER: S-EPMC4642276 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Differential recruitment of UBQLN2 to nuclear inclusions in the polyglutamine diseases HD and SCA3.

Zeng Li L Wang Bo B Merillat Sean A SA Minakawa Eiko N EN Perkins Matthew D MD Ramani Biswarathan B Tallaksen-Greene Sara J SJ Costa Maria do Carmo MDC Albin Roger L RL Paulson Henry L HL

Neurobiology of disease 20150630

Accumulation of mutant polyglutamine proteins in intraneuronal inclusions is a hallmark of polyglutamine diseases. Impairment of protein clearance systems and sequestration of clearance-related proteins into inclusions occur in many protein folding diseases, including polyglutamine diseases. The ubiquitin-binding and proteasome adaptor protein UBQLN2 participates in protein homeostasis and localizes to inclusions in various neurodegenerative diseases. Employing mouse models and human brain tissu ...[more]

PMID: 26141599

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Project description:BACKGROUND: Many cases of frontotemporal dementia (FTD) are familial, often with an autosomal dominant pattern of inheritance. Some are due to a mutation in the tau- encoding gene, on chromosome 17, and show an accumulation of abnormal tau in brain tissue (FTDP-17T). Most of the remaining familial cases do not exhibit tau pathology, but display neuropathology similar to patients with dementia and motor neuron disease, characterized by the presence of ubiquitin-immunoreactive (ub-ir), dystrophic neurites and neuronal cytoplasmic inclusions in the neocortex and hippocampus (FTLD-U). Recently, we described a subset of patients with familial FTD with autopsy-proven FTLD-U pathology and with the additional finding of ub-ir neuronal intranuclear inclusions (NII). NII are a characteristic feature of several other neurodegenerative conditions for which the genetic basis is abnormal expansion of a polyglutamine-encoding trinucleotide repeat region. The genetic basis of familial FTLD-U is currently not known, however the presence of NII suggests that a subset of cases may represent a polyglutamine expansion disease. METHODS: We studied DNA and post mortem brain tissue from 5 affected members of 4 different families with NII and one affected individual with familial FTLD-U without NII. Patient DNA was screened for CAA/CAG trinucleotide expansion in a set of candidate genes identified using a genome-wide computational approach. Genes containing CAA/CAG trinucleotide repeats encoding at least five glutamines were examined (n = 63), including the nine genes currently known to be associated with human disease. CAA/CAG tract sizes were compared with published normal values (where available) and with those of healthy controls (n = 94). High-resolution agarose gel electrophoresis was used to measure allele size (number of CAA/CAG repeats). For any alleles estimated to be equal to or larger than the maximum measured in the control population, the CAA/CAG tract length was confirmed by capillary electrophoresis. In addition, immunohistochemistry using a monoclonal antibody that recognizes proteins containing expanded polyglutamines (1C2) was performed on sections of post mortem brain tissue from subjects with NII. RESULTS: No significant polyglutamine-encoding repeat expansions were identified in the DNA from any of our FTLD-U patients. NII in the FTLD-U cases showed no 1C2 immunoreactivity. CONCLUSION: We find no evidence to suggest that autosomal dominant FTLD-U with NII is a polyglutamine expansion disease.

Dataset Information

Differential recruitment of UBQLN2 to nuclear inclusions in the polyglutamine diseases HD and SCA3.

Publications

Differential recruitment of UBQLN2 to nuclear inclusions in the polyglutamine diseases HD and SCA3.

Similar Datasets

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