Abstract
Intracellular aggregates are a common pathological hallmark of neurodegenerative diseases such as polyglutamine (polyQ) diseases, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and multiple system atrophy (MSA). Aggregates are mainly formed by aberrant disease-specific proteins and are accompanied by accumulation of other aggregate-interacting proteins. Although aggregate-interacting proteins have been considered to modulate the formation of aggregates and to be involved in molecular mechanisms of disease progression, the components of aggregate-interacting proteins remain unknown. In this study, we showed that small glutamine-rich tetratricopeptide repeat-containing protein alfa (SGTA) is an aggregate-interacting protein in neurodegenerative diseases. Immunohistochemistry showed that SGTA interacted with intracellular aggregates in Huntington disease (HD) cell models and neurons of HD model mice. We also revealed that SGTA colocalized with intracellular aggregates in postmortem brains of patients with polyQ diseases including spinocerebellar ataxia (SCA)1, SCA2, SCA3, and dentatorubral–pallidoluysian atrophy. In addition, SGTA colocalized with glial cytoplasmic inclusions in the brains of MSA patients, whereas no accumulation of SGTA was observed in neurons of PD and ALS patients. In vitro study showed that SGTA bound to polyQ aggregates through its C-terminal domain and SGTA overexpression reduced intracellular aggregates. These results suggest that SGTA may play a role in the formation of aggregates and may act as potential modifier of molecular pathological mechanisms of polyQ diseases and MSA.
Highlights
Formation of intracellular protein aggregates, which are microscopically observed as inclusion bodies, is a common pathological feature of neurodegenerative diseases including polyglutamine diseases, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and multiple system atrophy (MSA) [1, 2]
small glutamine-rich tetratricopeptide repeat-containing protein alfa (SGTA) colocalized with polyQ aggregates in Huntington disease (HD) model cells during aggregate formation First, we confirmed whether SGTA colocalizes with intracellular polyQ aggregates in HD model cells (HD150Q cells and HD150Q-nuclear translocation signals (NLS) cells)
In HD16Q and HD16Q-NLS cells, which were transfected with terminal huntingtin (tNhtt)-16Q or tNhtt-16Q-NLS, respectively, SGTA was diffusely distributed throughout the cytoplasm (Additional file 1, Fig. S1)
Summary
Formation of intracellular protein aggregates, which are microscopically observed as inclusion bodies, is a common pathological feature of neurodegenerative diseases including polyglutamine (polyQ) diseases, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and multiple system atrophy (MSA) [1, 2]. The main components of protein aggregates differ in each disease, In polyQ diseases, such as Huntington disease (HD) and several spinocerebellar ataxias (SCAs), aberrant proteins are produced by each causative gene harboring abnormally expanded polyQ tracts. These aberrant proteins change their conformation, repeat self-polymerization, and form insoluble aggregates [3]. PolyQ aggregates are composed of numerous aggregateinteracting proteins Some of these aggregate-interacting proteins are considered to be related to the process of aggregate formation and are widely associated with pathophysiology of various neurodegenerative diseases. The study of aggregate-interacting proteins could help to uncover molecular pathological mechanisms common to several neurodegenerative diseases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
