Abstract
Accumulation of aberrant proteins in inclusion bodies is a hallmark of many neurodegenerative diseases. Impairment of proteolytic systems is a common event in these protein misfolding diseases. Recently, mutations in the UBQLN 2 gene encoding ubiquilin 2 have been identified in X-linked amyotrophic lateral sclerosis (ALS). Furthermore, ubiquilin 2 is associated with inclusions in familial and sporadic ALS/dementia, synucleinopathies and polyglutamine diseases. Ubiquilin 2 exerts a regulatory role in proteostasis and thus it has been suggested that ubiquilin 2 pathology may be a common event in neurodegenerative diseases. Tauopathies, a heterogenous group of neurodegenerative diseases accompanied with dementia, are characterized by inclusions of the microtubule-binding protein tau. In the present study, we investigate whether ubiquilin 2 is connected with tau pathology in Alzheimer’s disease (AD), supranuclear palsy (PSP) and Pick’s disease (PiD) and familial cases with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We show that ubiquilin 2 positive inclusions are absent in these tauopathies. Furthermore, we find decreased ubiquilin 2 protein levels in AD patients, but our results do not indicate a correlation with tau pathology. Our data show no evidence for involvement of ubiquilin 2 and indicate that other mechanisms underly the proteostatic disturbances in tauopathies.
Highlights
Aggregation and accumulation of aberrant proteins is a common event in neurodegenerative diseases
To investigate whether ubiquilin 2 is involved in tau pathology, immunohistochemical analyses were performed on paraffin-embedded brain tissue from tauopathy patients and non-demented controls (Table 1)
We investigated whether ubiquilin 2 pathology described for amyotrophic lateral sclerosis (ALS)/ dementia is present in tau-related dementias (AD and FTD-tau), which are characterized by inclusions comprised of hyperphosphorylated tau
Summary
Aggregation and accumulation of aberrant proteins is a common event in neurodegenerative diseases. Neurons are post-mitotic cells that are highly dependent on efficient protein quality control systems to ensure protein homeostasis This includes protein folding, recognition and correction of misfolded proteins as well as degradation of terminally misfolded proteins by the proteolytic machinery consisting of the ubiquitinproteasome system and autophagy/lysosomal pathway [1]. Failure in proteolysis may lead to protein accumulation, buildup of protein intermediates, and formation of inclusion bodies. Impairment of both degradational pathways is implicated in neurodegeneration and provides a potential target for therapeutic intervention. The ubiquitinbinding protein ubiquilin 2 has been linked to amyotrophic lateral sclerosis (ALS), a rapidly progressive motoneuron disease, which is in about 20% of patients accompanied by frontotemporal dementia [2].
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