piRNA/PIWI Protein Complex as a Potential Biomarker in Sporadic Amyotrophic Lateral Sclerosis

Abstract

The pathological hallmark of the majority of amyotrophic lateral sclerosis (ALS) cases is the mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43), an RNA-binding protein. Several studies have attributed disease processes of ALS to abnormal RNA metabolism. However, dysregulated biogenesis of RNA, especially non-coding RNA (ncRNA), is poorly understood. To resolve it, RNA-Seq, biochemical, and immunohistochemical analyses were performed on the pyramidal tract of the medulla oblongata of sporadic ALS (sALS) and control postmortem brain samples. Here, we report perturbation of ncRNA biogenesis in PIWI-interacting RNA (piRNA) in several sALS brain samples associated with TDP-43 pathology. In addition, we confirmed the dysregulation of two PIWI homologs, PIWI-like-mediated gene silencing 1 (PIWIL1) and PIWIL4, which bind to piRNAs to regulate their expression. PIWIL1 was mislocalized and co-localized with TDP-43 in motor neurons of sporadic ALS lumbar cords. Our results imply that dysregulation of piRNA, PIWIL1, and PIWIL4 is linked to pathogenesis of ALS. Based on these results, piRNAs and PIWI proteins are potential diagnostic biomarkers and therapeutic targets of ALS.

Progressive Irreversible Proprioceptive Piezo2 Channelopathy-Induced Lost Forced Peripheral Oscillatory Synchronization to the Hippocampal Oscillator May Explain the Onset of Amyotrophic Lateral Sclerosis Pathomechanism

“…Nevertheless, the genetic background of ALS is still quite obscure, because the heritability of sporadic patients is estimated to be as high as 50% [ 4 ]. Accordingly, the contribution of long non-coding DNA and RNA is linked to the ALS disease process [ 5 , 6 , 7 ], and this is how, for example, the dysregulation of piRNA/PIWI proteins could have a role in ALS pathogenesis [ 8 ]. The majority of the genes associated with ALS are either susceptibility factors or genes linked to other neurodegenerative conditions; hence, they have no direct causal relationship with ALS.…”

Role of piRNA biogenesis and its neuronal function in the development of neurodegenerative diseases

“…In human brains with sporadic ALS, three piRNAs, hsa-piR-000578 , hsa-piR-020871 , and hsa-piR-022184 , were upregulated, whereas two piRNAs, hsa-piR-009294 and hsa-piR-016735 , were downregulated ( Abdelhamid et al, 2022 ; Table 1 ). The expression level of HIWI/PIWIL1 was also increased in sporadic ALS brain tissues, whereas that of HIWI2/PIWIL4 was decreased ( Abdelhamid et al, 2022 ).…”

“…In human brains with sporadic ALS, three piRNAs, hsa-piR-000578 , hsa-piR-020871 , and hsa-piR-022184 , were upregulated, whereas two piRNAs, hsa-piR-009294 and hsa-piR-016735 , were downregulated ( Abdelhamid et al, 2022 ; Table 1 ). The expression level of HIWI/PIWIL1 was also increased in sporadic ALS brain tissues, whereas that of HIWI2/PIWIL4 was decreased ( Abdelhamid et al, 2022 ). Furthermore, HIWI/PIWIL1 proteins were co-localized with TDP-43 in the motor neurons of sporadic ALS lumbar cords, suggesting that HIWI/PIWIL1 may contribute to the formation of TDP-43 inclusions ( Abdelhamid et al, 2022 ).…”

“…The expression level of HIWI/PIWIL1 was also increased in sporadic ALS brain tissues, whereas that of HIWI2/PIWIL4 was decreased ( Abdelhamid et al, 2022 ). Furthermore, HIWI/PIWIL1 proteins were co-localized with TDP-43 in the motor neurons of sporadic ALS lumbar cords, suggesting that HIWI/PIWIL1 may contribute to the formation of TDP-43 inclusions ( Abdelhamid et al, 2022 ). In addition, the expression level of the piRNA, hsa-piR-33151 , has been reported to be decreased in the serum of patients with ALS ( Waller et al, 2017 ).…”

Novel roles of PIWI proteins and PIWI-interacting RNAs in human health and diseases

“…Previous research has implicated the crucial role of PIWIL1 in neuronal development and protection in the migration of microtubules [ 355 ]. This observation suggested that PIWIL1 expression change can act as a compensatory mechanism for axonal dysfunction [ 356 ].…”