Grb2 Is Regulated by Foxd3 and Has Roles in Preventing Accumulation and Aggregation of Mutant Huntingtin

Shounak Baksi,Debashis Mukhopadhyay,Nitai Pada Bhattacharyya,Nihar R Jana,Kah-Leong Lim

doi:10.1371/journal.pone.0076792

Shounak Baksi, Debashis Mukhopadhyay + Show 3 more

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https://doi.org/10.1371/journal.pone.0076792

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Abstract

Growth factor receptor protein binding protein 2 (Grb2) is known to be associated with intracellular growth and proliferation related signaling cascades. Huntingtin (Htt), a ubiquitously expressed protein, when mutated, forms toxic intracellular aggregates - the hallmark of Huntington’s disease (HD). We observed an elevated expression of Grb2 in neuronal cells in animal and cell models of HD. Grb2 overexpression was predominantly regulated by the transcription factor Forkhead Box D3 (Foxd3). Exogenous expression of Grb2 also reduced aggregation of mutant Htt in Neuro2A cells. Grb2 is also known to interact with Htt, depending on epidermal growth factor receptor (EGFR) activation. Grb2- mutant Htt interaction in the contrary, took place in vesicular structures, independent of EGFR activation that eventually merged with autophagosomes and activated the autophagy machinery helping in autophagosome and lysosome fusion. Grb2, with its emerging dual role, holds promise for a survival mechanism for HD.

Highlights

Several neurodegenerative diseases are caused by the increase in number of glutamine in specific genes, known as polyQ expansion diseases
In order to find out where this extra Growth factor receptor protein binding protein 2 (Grb2) was going, we investigated the levels of autophagy related proteins in STHdhQ111/111 cells and the two autophagy markers LC3, Beclin1 and late endosomal marker Rab7 were found to be significantly upregulated in the Huntington’s disease (HD) cell model (Figure 2C,D; p
It is demonstrated that endogenous Grb2 is upregulated in HD R6/2 mouse model as well as in a cell model STHdhQ111/111, precluding the possibility of secondary effects

Summary

Introduction

Several neurodegenerative diseases are caused by the increase in number of glutamine (polyQ) in specific genes, known as polyQ expansion diseases. Huntington’s disease (HD), the most well studied amongst nine such neurodegenerative disorders, is caused by polyQ expansion in the protein huntingtin (Htt) [1]. Growth factor receptor protein binding protein 2 (Grb2) is known to be an interactor of Htt and this interaction is reported to be regulated by the activation of epidermal growth factor (EGF) receptors [5]. Grb is thought to link intracellular signaling cascades and activated receptor tyrosine kinases, like Trk receptors, and regulate neural survival, development, function, and plasticity [9]. Reports from transgenic and knockout animal models, protein-protein-interaction studies and the discovery of a plethora of Htt interactors suggest that Htt might act as a multifunctional scaffold during the process of clathrin-mediated endocytosis, neuronal transport processes and post synaptic signaling [10]

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