Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder that progressively affects motor neurons in the brain and spinal cord. Due to the biological complexity of the disease, its etiology remains unknown. Several cellular mechanisms involved in the neurodegenerative process in ALS have been found, including the loss of RNA and protein homeostasis, as well as mitochondrial dysfunction. Insoluble protein aggregates, damaged mitochondria, and stress granules, which contain RNA and protein components, are recognized and degraded by the autophagy machinery in a process known as selective autophagy. Autophagy is a highly dynamic process whose dysregulation has now been associated with neurodegenerative diseases, including ALS, by numerous studies. In ALS, the autophagy process has been found deregulated in both familial and sporadic cases of the disease. Likewise, mutations in genes coding for proteins involved in the autophagy machinery have been reported in ALS patients, including selective autophagy receptors. In this review, we focus on the role of selective autophagy in ALS pathology.

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 (SOD1 G93A and TDP43 A315T ) 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. Electronic supplementary material The online version of this article (10.1186/s13024-019-0313-9) contains supplementary material, which is available to authorized users.

Background and Objective Over the past few years, the importance of interleukin‐22 (IL‐22) and T‐helper (Th)22 lymphocytes in the pathogenesis of periodontitis has become apparent; however, there are still aspects that are not addressed yet. Cells expressing IL‐22 and aryl hydrocarbon receptor (AhR), transcription factor master switch gene implicated in the differentiation and function of Th22 lymphocytes, have been detected in periodontal tissues of periodontitis‐affected patients. In addition, IL‐22 has been associated with osteoclast differentiation and their bone resorptive activity in vitro. However, the destructive potential of IL‐22–expressing AhR+ Th22 lymphocytes over periodontal tissues during periodontitis has not been demonstrated in vivo yet. Therefore, this study aimed to analyze whether IL‐22–expressing CD4+AhR+ T lymphocytes detected in periodontal lesions are associated with alveolar bone resorption during experimental periodontitis. Material and Methods Using a murine model of periodontitis, the expression levels of IL‐22 and AhR, as well as the Th1‐, Th2‐, Th17‐ and T regulatory‐associated cytokines, were analyzed in periodontal lesions using qPCR. The detection of CD4+IL‐22+AhR+ T lymphocytes was analyzed in periodontal lesions and cervical lymph nodes that drain these periodontal lesions using flow cytometry. In addition, the expression of the osteoclastogenic mediator called receptor activator of nuclear factor‐κB ligand (RANKL) was analyzed by qPCR, western blot, and immunohistochemistry. Finally, alveolar bone resorption was analyzed using micro‐computed tomography and scanning electron microscopy, and the bone resorption levels were correlated with IL‐22 and RANKL expression. Results Higher levels of IL‐22, AhR, and RANKL, as well as IL‐1β, IL‐6, IL‐12, IL‐17, IL‐23, and TNF‐α, were expressed in periodontal lesions of infected mice compared with periodontal tissues of sham‐infected and non‐infected controls. Similarly, high RANKL immunoreaction was observed in periodontal tissues of infected mice; however, few or absent RANKL immunoreaction was observed in controls. This association between RANKL and periodontal infection was ratified by western blot. Furthermore, a higher detection of CD4+IL‐22+AhR+ T lymphocytes was found in periodontal lesions and cervical lymph nodes that drain these periodontal lesions in infected mice compared with non‐infected controls. Finally, the increased IL‐22 and RANKL expression showed positive correlation between them and with the augmented alveolar bone resorption observed in experimental periodontal lesions. Conclusion This study demonstrates the increase of IL‐22–expressing CD4+AhR+ T lymphocytes in periodontitis‐affected tissues and shows a positive correlation between IL‐22, RANKL expression, and alveolar bone resorption.

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The adverse environmental conditions found in the periodontium during periodontitis pathogenesis stimulate local autophagy responses, mainly due to a continuous inflammatory response against the dysbiotic subgingival microbiome. The junctional epithelium represents the main site of the initial interaction between the host and the dysbiotic biofilm. Here, we investigated the role of autophagy in junctional epithelium keratinocytes (JEKs) in response to Aggregatibacter actinomycetemcomitans or its purified lipopolysaccharides (LPS). Immunofluorescence confocal analysis revealed an extensive nuclear translocation of transcription factor EB (TFEB) and consequently, an increase in autophagy markers and LC3-turnover assessed by immunoblotting and qRT-PCR. Correspondingly, challenged JEKs showed a punctuate cytosolic profile of LC3 protein contrasting with the diffuse distribution observed in untreated controls. Three-dimensional reconstructions of confocal images displayed a close association between intracellular bacteria and LC3-positive vesicles. Similarly, a close association between autophagic vesicles and the protein p62 was observed in challenged JEKs, indicating that p62 is the main adapter protein recruited during A. actinomycetemcomitans infection. Finally, the pharmacological inhibition of autophagy significantly increased the number of bacteria-infected cells as well as their death, similar to treatment with LPS. Our results indicate that A. actinomycetemcomitans infection induces autophagy in JEKs, and this homeostatic process has a cytoprotective effect on the host cells during the early stages of infection.