Miro1 overexpression protects against α-synuclein-induced mitochondrial loss in neuronal culture

Dzhamilja Safiulina,Vinay Choubey,Allen Kaasik,Miriam Ann Hickey

doi:10.1186/2193-1801-4-s1-p41

Abstract

Mitophagy is a selective degradation of mitochondria that promotes the turnover of mitochondria and prevents the accumulation of damaged organelles. Pink1 and Parkin proteins are crucial in the removal of damaged mitochondria. Mutations in the corresponding PINK1 and PARK2 genes are associated with Parkinson’s disease (PD), and mitochondrial impairments are central to PD pathogenesis. Pink1 has been shown to interact with the atypical Rho GTPases Miro, the outer mitochondrial membrane proteins involved in mitochondrial trafficking. Miro1 is degraded shortly after mitochondrial damage in a Parkin-dependent manner. α-synuclein is a major component of Lewy bodies, the characteristic cellular inclusions in PD. Mutations of α-synuclein, including A53T, are linked to familial PD. α-synuclein has been shown to bind to the mitochondrial membrane, and increased membrane-bound α-synuclein in PD contributes to the functional disturbance of mitochondria. Overexpression of A53T-mutated α-synuclein has been shown to induce mitophagy in vitro and in vivo. We hypothesized that Miro1 function is disturbed in an α-synuclein (A53T)-overexpressing model, and the aim of this study was to elucidate the involvement of Miro1 in α-synuclein-induced mitophagy. We have found that α-synuclein is one component of the Miro1 interactome. Moreover, co-expression of Miro1 restored mitochondrial length and density in primary neuronal culture overexpressing A53T-mutated α-synuclein. Miro1 overexpression did not change the basal mitophagy, but decreased significantly α-synuclein-induced mitochondrial removal. Together, our results suggest that Miro and α-synuclein may interact in the mitophagic pathway.

Highlights

Alzheimer’s disease (AD) is an incurable neurodegenerative disease characterized by progressive dementia
The results of the present study indicate that development of the neuronal hypoxic tolerance induced by the three-trial, in contrast to one-trial, mild hypoxic preconditioning is apparently largely associated with the activation of CREB, as well as brain-derived neurotrophic factor (BDNF) and Bcl-2 overexpression
No significant differences in serum level of Solubile form of RAGE (sRAGE) where found between rapidly progressing and slow progressing subgroup of multiple sclerosis (MS) patients.Our results suggest for the role of sRAGE in MS ethiopathogenesis, but we did not find any association of sRAGE in serum with the rate of MS disability progression

Summary

Introduction

Alzheimer’s disease (AD) is an incurable neurodegenerative disease characterized by progressive dementia. The aim of the study was to characterize the effects of streptozocin (STZ)-indced diabetes on learning and memory of 5XFAD and wild-type (WT) mice in Morris water maze (MWM) at ages 2 and 6 months and on brain amyloid load. Existing evidence suggests GABAergic system is involved in pathophysiology of Alzheimer’s disease (AD) via inhibitory interneuron deficits (Verret et al, 2012) and decrease in functional GABAA receptors (Limon et al, 2012). Our concept: low doses of muscimol may prevent learning/memory deficits in intracerebroventricular (icv) streptozocin (STZ)-induced AD nontransgenic rat model. The Sigma-1 receptor is a chaperone protein that modulates intracellular calcium signalling of the endoplasmatic reticulum and is involved in learning and memory processes.The aim of the present study was to compare in vitro Ca2+ concentration modulating activity and in vivo behavioural effects of enantiomers of methylphenylpiracetam, a novel positive allosteric modulator of Sigma-1 receptors

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