Introduction

Neurodegenerative disorders (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), and tauopathies represent a significant public health burden both in Colombia and globally due to their high prevalence and the progressive neurological decline they cause ^1-6. Despite advances in understanding these diseases, the molecular mechanisms underlying their pathogenesis remain largely unknown, limiting the development of effective treatments and early diagnostic tools ⁷. Traditionally, neurodegeneration research has focused on pathological proteins such as ß-amyloid, hyperphosphorylated tau, and α-synuclein ^3,8. However, the growing interest in non-coding RNAs, such as microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs), has opened new avenues of research with the potential to revolutionize our understanding of these diseases ^9-13.

piRNAs, a class of small non-coding RNAs, were initially discovered in germ cells, where they play a fundamental role in maintaining genomic stability by silencing transposable elements ^14-17. piRNAs interact with PIWI-like proteins, forming complexes that not only regulate genome stability but also participate in gene expression regulation and epigenetic modulation at a multisystemic level, including the central nervous system (CNS) ^{7,8,11,18,19,20}.

Non-regulation of piRNAs has been reported in transcriptomic studies of human brains and animal models of diseases such as AD and PD, and it has been proposed that the loss of functional piRNAs may contribute to neurodegeneration through the activation of transposable elements, alteration of protein degradation, and failure in the regulation of key epigenetic pathways ^9,10,19,20. Furthermore, PIWI-like proteins and piRNAs have begun to be considered as potential biomarkers for early diagnosis of these diseases and new therapeutic targets.

In this context, this systematic review seeks to gather and examine the existing evidence on the role of piRNAs in neurodegenerative diseases, along with the molecular mechanisms by which they contribute to the pathogenesis of conditions like AD, PD, ALS, and tauopathies, aiming also to assess their potential as diagnostic and therapeutic biomarkers.

Methods

This systematic review aimed to assess an up-to-date overview of the piRNA role in neurodegenerative diseases. Adhering to PRISMA 21-22 guidelines, the review followed a structured approach:

Results

We conducted a literature search in two databases (PubMed and ScienceDirect) and identified 47 relevant papers. After confirming no duplicates (n = 0), we screened titles and abstracts (n = 47) and excluded review articles and unrelated studies (n = 36).

Ultimately, 11 studies were included in this systematic review (Figure 1).

Figure 1: PRISMA flow chart

Source: Own elaboration based on ^21,22.

Our research analyzed 11 articles that demonstrate the relation between piRNAs with the neurodegenerative diseases (Table 2).

Huang et al. ¹ revealed dysregulation of piRNAs in Caenorhabditis elegans models of Lewy body disease. Using transgenic strains overexpressing α-synuclein and a combination of α-synuclein and ß-amyloid, they observed that the elimination of piRNA biogenesis genes, such as tofu-1, significantly improved motor behavior in these models. These findings suggest that piRNAs may be related to the regulation of protein degradation, a crucial process in the progression of neurodegenerative diseases. Moreover, studies in human brain samples from patients with advanced Parkinson's disease showed overexpression of piRNAs, suggesting an association between piRNA dysfunction and Lewy body-related disorders and PD (Figure 2) ^1,8,11.

Figure 2: In vivo models for detection of dysregulation of piRNAs

Source: ^1-3.

The transcriptomic analysis by Zhang and Wong ² on Parkinson's disease revealed that somatic piRNAs are dysregulated in different Parkinson's subtypes and in varied Parkinson's-related diseases, such as Parkinson's disease dementia (PDD), and across different stages of the disease, from premotor to motor stages. They identified 902 somatic piRNAs, 527 of which were present in the brain, suggesting a relevant role for these piRNAs in the nervous system. Specific piRNAs, such as piR-has-92056 and piR-hsa-1909905, were highlighted as diagnostic bio-markers with high accuracy (AUC = 0.89), reinforcing their potential for early diagnosis of PD ^2,7.

Using Drosophila melanogaster and postmortem human brain samples from Alzheimer's and progressive supranuclear palsy (PSP) patients, Sun et al. ³ explored the interaction between piRNAs and transposable elements in tauopathies. Their results showed that piRNA depletion promotes the dysregulation of transposable elements, contributing to neuronal death. The loss of piRNAs in these diseases is associated with heterochromatin decondensation, which allows the activation of transposable elements, implicating piRNAs in maintaining genomic stability in neurons affected by tauopathies.

Qiu et al. ⁷ conducted a transcriptomic profile of human brains from Alzheimer's patients, identifying over 9,400 piRNAs in the brain, 103 of which were expressed between AD cases and controls. These piRNAs were correlated with previously identified genetic risk SNPs for Alzheimer's, suggesting that piRNAs are directly involved in regulating pathogenic pathways in AD ^7,9. The study also highlighted the abundance of piRNAs in the human brain, suggesting their role in neurodegeneration could be broader than previously thought.

Jain et al. ⁸ expanded the understanding of piRNAs in AD by discovering a combined signature of three piRNAs and three miRNAs that was capable of detecting AD pathology with significant accuracy (AUC = 0.83). Additionally, their analysis predicted the conversion of patients with mild cognitive impairment to Alzheimer's dementia with even higher accuracy (AUC = 0.86). These findings suggest that piRNAs are not only involved in AD pathogenesis but also hold significant potential as biomarkers for early diagnosis and disease progression monitoring ^8,12.

Regarding amyotrophic lateral sclerosis (ALS), Abdelhamid et al. ⁵ reported that piRNA dysfunction is linked to TDP-43 pathology in ALS patients ^5,13,14. They identified that PIWI-like proteins 1 and 4 (PIWIL1 and PIWIL4), which are involved in piRNA biogenesis, were dysregulated in motor neurons affected by ALS. This suggests that piRNA dysfunction may contribute to the neurodegenerative process in ALS, marking a new potential therapeutic target for this devastating disease.

Simoes et al. ⁶ focused on progressive supranuclear palsy, where they found significant dysregulation of the piRNA hsa-piR-31068 in both serum and cerebrospinal fluid (CSF) of PSP patients ^6,9,14. This dysregulation could serve as a distinctive disease marker, suggesting that piRNAs have the potential to be used as biomarkers in biofluids, facilitating earlier and more precise diagnosis of PSP.

In the context of Alzheimer's disease pathogenesis, Schulze et al. ⁹ documented that differentiated neuronal cells derived from patients with sporadic Parkinson's disease showed abundant piRNA dysregulation. These results provide further evidence that piRNAs are important regulators of neuronal homeostasis and that their dysfunction may be central to neurodegeneration in various diseases, including Parkinson's and Alzheimer's ⁹.

Finally, Roy et al. ¹⁰ proposed that PIWI proteins, which interact with piRNAs, could act as a molecular bridge between the blood-brain barrier and neuro-pathological conditions ^10,18. They suggest that piRNAs and PIWI proteins are involved in regulating neuronal homeostasis, and their dysfunction may precede the onset of neurodegenerative diseases.

Discussion

The accumulated evidence across these studies underscores the central relevance of piRNAs in various neurodegenerative diseases. Mechanistically, piRNAs appear to play a multifaceted role in neuronal homeostasis, acting as regulators of gene expression, genomic stability, and protection against transposable elements. The dysfunction of piRNAs observed in diseases such as Alzheimer's, Parkinson's, and tauopathies highlights a pathogenic convergence point: the loss of control over transposable elements and the dysregulation of RNA processing (Figure 3) ^7-9.

Figure 3: piRNA association with neurodegenerative diseases

Source: ^7-9.

Huang et al. ¹ demonstrated that piRNA dysfunction in Lewy body disease models is not only correlated with the disease but that manipulation of piRNA biogenesis genes has protective effects on motor behavior, pointing to a potential therapeutic approach ^1,21-22. In this regard, the findings by Zhang and Wong ² in Parkinson's disease also highlight the role of piRNAs as diagnostic biomarkers, suggesting that piRNAs could be used to identify subtypes and related diseases, and monitor its progression ^2,23,24.

Research on tauopathies ³ and AD ^7,8 reinforces the idea that piRNAs are essential for genomic integrity in neurons and that their dysfunction can trigger pathogenic cascades culminating in neuronal death. The observation that piRNAs are involved in transposable element dysregulation suggests that these small RNAs could be a viable therapeutic target for preventing or delaying neurodegeneration ^3,7,8,25,26.

The discovery of piRNA dysfunction in ALS ⁵ and PSP ⁶ expands the spectrum of neurodegenerative diseases where piRNAs could serve as biomarkers or therapeutic targets. Studies in ALS highlight that PIWI protein dysregulation is correlated with TDP-43 pathology, a key marker of ALS. This finding opens new avenues for the exploration of piRNA-and PIWI-targeted therapies in ALS ^7,8,27-30.

In the Colombian context, the implementation of piRNA-based therapies for neurodegenerative diseases faces certain challenges regarding feasibility and coverage. Introducing these innovative therapies would require advanced infrastructure and trained personnel, which may be limited in the short term. However, collaborations with international institutions could facilitate clinical trials within the country, creating a pathway for eventual integration into specialized centers. Although initial costs could limit access in early stages, it is essential to explore strategies to ensure equitable access within the healthcare system. Finally, while piRNA-based therapies hold great potential, they should not replace the importance of preventive interventions. Ideally, piRNA therapies could complement preventive strategies, working together to reduce the burden of neurode-generative diseases across the population.

Conclusions

piRNAs have emerged as essential regulators in neurodegeneration, playing a complex role in preserving neuronal homeostasis by modulating transposable elements, protein degradation, and genomic stability. The reviewed studies indicate that piRNA dysfunction is a common characteristic across various neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and tauopathies. As research continues to elucidate the molecular mechanisms by which piRNAs contribute to these pathologies, the potential for developing piRNA-based diagnostic tools and therapeutic approaches is expanding.

The identification of specific piRNA signatures in neurodegenerative diseases marks a significant step towards precision medicine, offering the possibility of earlier and more accurate diagnoses. Additionally, the modulation of piRNA and PIWI protein activity presents a novel and promising therapeutic approach that could transform the management of neurode-generative disorders. Targeting piRNA pathways to restore neuronal homeostasis or prevent neurodegeneration opens new avenues for treatment, especially in diseases for which no curative therapies currently exist.

As the understanding of piRNAs continues to evolve, these small non-coding RNAs hold the potential to reshape both the diagnostic landscape and therapeutic strategies for neurodegenerative diseases, providing new hope for patients affected by these devastating conditions. It is crucial to strengthen both innovative therapies and preventive strategies within the Colombian context, particularly for neurodegenerative diseases. While piRNA therapies are promising, they should be viewed as complementary to established preventive interventions, ensuring comprehensive and equitable care throughout the country.