RESUMO
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a multifactorial fatal motoneuron disease without a cure. Ten percent of ALS cases can be pointed to a clear genetic cause, while the remaining 90% is classified as sporadic. Our study was aimed to uncover new connections within the ALS network through a bioinformatic approach, by which we identified C13orf18, recently named Pacer, as a new component of the autophagic machinery and potentially involved in ALS pathogenesis. METHODS: Initially, we identified Pacer using a network-based bioinformatic analysis. Expression of Pacer was then investigated in vivo using spinal cord tissue from two ALS mouse models (SOD1G93A and TDP43A315T) and sporadic ALS patients. Mechanistic studies were performed in cell culture using the mouse motoneuron cell line NSC34. Loss of function of Pacer was achieved by knockdown using short-hairpin constructs. The effect of Pacer repression was investigated in the context of autophagy, SOD1 aggregation, and neuronal death. RESULTS: Using an unbiased network-based approach, we integrated all available ALS data to identify new functional interactions involved in ALS pathogenesis. We found that Pacer associates to an ALS-specific subnetwork composed of components of the autophagy pathway, one of the main cellular processes affected in the disease. Interestingly, we found that Pacer levels are significantly reduced in spinal cord tissue from sporadic ALS patients and in tissues from two ALS mouse models. In vitro, Pacer deficiency lead to impaired autophagy and accumulation of ALS-associated protein aggregates, which correlated with the induction of cell death. CONCLUSIONS: This study, therefore, identifies Pacer as a new regulator of proteostasis associated with ALS pathology.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Autofagia/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Neurônios Motores/metabolismo , Esclerose Lateral Amiotrófica/genética , Animais , Modelos Animais de Doenças , Humanos , Camundongos Transgênicos , Medula Espinal/metabolismo , Medula Espinal/patologia , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismoRESUMO
INTRODUCTION: Tinnitus is usually associated with hearing loss, and patients with tinnitus and normal hearing are unusual. Neuro-otological findings have not previously been described in tinnitus patients with normal hearing. AIM: To analyse neuro-otological examination results from a group of tinnitus patients with normal hearing. MATERIALS AND METHODS: Seventeen normal-hearing tinnitus patients seen over a 10-year period were retrospectively evaluated. Their results were compared with those of a control group of 17 normal subjects without tinnitus. RESULTS: The main neuro-otological finding in the tinnitus patients was caloric test abnormality: a unilateral canal paresis was present in 15 of the 17 patients. Caloric tests were normal in 15 of the 17 control subjects. CONCLUSION: We may infer from these results that tinnitus could be the only clinical manifestation of a cochlear - and presumably cochleo-vestibular - lesion, and that unilateral canal paresis may be the only abnormal finding on neuro-otological examination.