Jamshed Arslan, Pharm D, PhD
Neurodegenerative disorders involve loss of function and, ultimately, death of neurons. Selective neuronal vulnerability has been observed in a variety of neurodegenerative diseases. For example, amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2) attack motor neurons, while Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) primarily destroy pyramidal neurons, dopaminergic neurons, and medium spiny GABAergic neurons, respectively. Immense research is underway to determine a common pathway underlying these disorders. Over the years, Dr. Stefan Pulst and his team at the University of Utah, USA, have discovered that abundance of Staufen1 (STAU1) – an RNA-binding, stress granule protein – underlies the pathology of SCA2 and ALS. The research group set out to explore if STAU1 is implicated in other neurodegenerative diseases including AD, PD, and HD. Through a series of experiments using cell lines, animal models and human postmortem samples, Dr Pulst’s team found that STAU1 overabundance, and the consequent hyperactive mTOR signaling, is among the signs of neurodegeneration.
Immunofluorescence image of in vitro day 9 rat E18 primary hippocampal neuron cells. Cells were fixed in 4% paraformaldehyde at RT and then staining with Rabbit Anti-Staufen Polyclonal Antibody (NBP1-33202) at 1:500 (green) and Beta Tubulin 3/ Tuj1 Antibody  at 1:500 (red). Nuclear staining performed by Fluoroshield with DAPI (blue).
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Excess STAU1 is Associated with mTOR Hyperactivity in Neurodegeneration
To detect the abundance of STAU1, the team utilized patient cell lines containing one or more hallmark mutations of neurodegenerative diseases. Western blots revealed a 3-6 fold increase in STAU1. This was associated with 3-4 fold increase in a master regulator of autophagy known as mTOR, without increased mRNA levels of STAU1 or mTOR. This indicated a reduced autophagosomal degradation of STAU1 in the presence of mutated proteins. These results were corroborated by SCA2 and ALS mouse models.
The next step was to see if neurodegeneration-related proteins are responsible for the increase in STAU1 levels and to determine if mTOR hyperactivity could be reduced by blocking excessive STAU1.
Immunohistochemical staining of rat brain tissue section with Rabbit Anti-LC3B Polyclonal Antibody (NB100-2220). Image from verified customer review.
Neurodegeneration Causes STAU1 Overabundance
To establish a causal relationship between neurodegeneration-related proteins and STAU1 overabundance, the researchers employed multiple experimental approaches, including: 1) expressing disease-related mutations in human cells; 2) silencing disease-related genes using siRNA; and 3) exogenously expressing tagged-STAU1 in wild-type cells. The results showed that disease-related proteins cause STAU1 overabundance, which in turn leads to hyperactive mTOR signaling.
To determine if mTOR hyperactivity could be mitigated, the team knocked down STAU1 in the cells that overexpressed STAU1. As predicted, silencing STAU1 normalized mTOR and its downstream targets.
In sum, mutated proteins related to ALS, SCA2, AD, PD, and HD cause the STAU1 to increase, which in turn leads to mTOR hyperactivity and eventual death of the neurons.
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This paper describes the discovery of a major pathway underlying multiple neurodegenerative diseases. Based on this preliminary research, clinical trials are warranted to determine whether STAU1 is potential biomarker of neurodegeneration, and to prove if blocking STAU1 with viral vectors or RNA-interference is a viable approach to mitigate neurodegeneration in humans.
Paul, S. et al. (2021) used Rabbit Anti-Staufen Polyclonal Antibody (NBP1-33202), Rabbit Anti-LC3B Polyclonal Antibody (NB100-2220), and Rabbit Anti-G3BP1 Polyclonal Antibody (NBP1-18922).
Jamshed Arslan, Pharm D, PhD
Dr Arslan is an Assistant Professor at Salim Habib University (formerly, Barrett Hodgson University), Pakistan. His interest lies in neuropharmacology and preparing future pharmacists.
Research in Focus
Paul, S., Dansithong, W., Figueroa, K. P., Gandelman, M., Scoles, D. R., & Pulst, S. M. (2021). Staufen1 in Human Neurodegeneration. Annals of neurology. https://doi.org/10.1002/ana.26069