Abstract
The Rho guanine nucleotide exchange factor (RGNEF) protein encoded by the ARHGEF28 gene has been implicated in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Biochemical and pathological studies have shown that RGNEF is a component of the hallmark neuronal cytoplasmic inclusions in ALS-affected neurons. Additionally, a heterozygous mutation in ARHGEF28 has been identified in a number of familial ALS (fALS) cases that may give rise to one of two truncated variants of the protein. Little is known about the normal biological function of RGNEF or how it contributes to ALS pathogenesis. To further explore RGNEF biology we have established and characterized a yeast model and characterized RGNEF expression in several mammalian cell lines. We demonstrate that RGNEF is toxic when overexpressed and forms inclusions. We also found that the fALS-associated mutation in ARGHEF28 gives rise to an inclusion-forming and toxic protein. Additionally, through unbiased screening using the split-ubiquitin system, we have identified RGNEF-interacting proteins, including two ALS-associated proteins. Functional characterization of other RGNEF interactors identified in our screen suggest that RGNEF functions as a microtubule regulator. Our findings indicate that RGNEF misfolding and toxicity may cause impairment of the microtubule network and contribute to ALS pathogenesis.
Highlights
Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease caused by loss of upper and lower motor neurons in the brain and spinal cord [1]
Our results indicate that Rho guanine nucleotide exchange factor (RGNEF) can undergo toxic misfolding and that it interacts with the microtubule network, which may contribute to neurotoxicity and to neurodegeneration in ALS
These findings suggest a functional link between RGNEF and the microtubule network that may be compromised by RGNEF misfolding and aggregation in ALS
Summary
Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease caused by loss of upper and lower motor neurons in the brain and spinal cord [1]. Since the discovery of ALS mutations in SOD1, more than twenty-six genes have been identified as causative for fALS [3,4]. Many of these proteins are involved in RNA metabolism, including C9orf, Tar DNA binding protein (TDP-43), and fused in sarcoma (FUS) [3,4]. Most sALS cases are not linked to any known mutations Environmental insults, such as changes in pH and exposure to toxic chemicals or excessive oxidative stress, can lead to protein misfolding that may contribute to neurodegeneration in ALS [12,13]. The highest risk factor for most neurodegenerative diseases is advanced age, indicating that the physiological changes associated with aging contribute to disease-related protein misfolding [14]
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