NEAT1 on the Field of Parkinson’s Disease: Offense, Defense, or a Player on the Bench?

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. Considering the devastating symptoms, high prevalence, and lack of definitive diagnostic test, there is an urgent need to identify possible biomarkers and new therapeutic targets. Genes identified and/or proposed to be linked to PD encode proteins that fulfill diverse roles in cellular functions. There is a growing interest in identifying common traits which lead to the disease. Long non-coding RNAs have recently emerged as possible regulatory hubs of complex molecular changes affecting PD development. Among them, NEAT1 has attracted particular interest. It is a major component and the initiator of nuclear paraspeckles, thus regulating transcription and modifying protein functions. This review summarizes data available on the role of NEAT1 in PD. NEAT1 upregulation in PD has repeatedly been reported, however, whether this is part of a protective or a damaging mechanism is still a topic of debate. It has been proposed that NEAT1 propagates PD via its interaction with PINK1 and several micro RNAs and by modulating SNCA expression. On the other hand, findings of NEAT1 acting as a bona fide LRRK2 inhibitor argue for its protective role. These contradictory results could be due to the different disease models implemented. This calls attention to the difficulties posed by the complex patho-mechanisms of neurodegenerative disorders and the limitations of disease models. However, the potential of NEAT1 as a biomarker and as a therapeutic target for PD highly warrants further research to elucidate its exact role in this neurodegenerative disorder.

Novel Insights into the Emerging Role of Neat1 and Its Effects Downstream in the Regulation of Inflammation

“…Neat1_1 is high abundance and exhibits a high expression in a wide range of tissues. 19 Nonetheless, in contrast to the Neat1_2 isoform, the shorter Neat1_1 isoform has no an integral element of paraspeckles; however, it appears as microspeckles and thus may contain other effects that have not been discovered. 43 Additionally, Sasaki et al 45 indicated that the knockdown of the production of Neat1_2 can lead to paraspeckle elimination even in the presence of intact Neat1_1.…”

“… 42 , 43 Paraspeckle is a complex consisting of subnuclear ribonucleoprotein within interchromatin, which plays a vital role in modulating transcription and RNA processing mainly via regulating RNA and protein editing and serving as a sponge targeting to various microRNAs. 19 There are two subtypes of mono-exonic isoforms transcribed from the Neat1 locus from chromosome 11, known as shorter Neat1_1 with 3684 nucleotides and longer Neat1_2 with 22,743 nucleotides. 19 , 44 The shorter Neat1_1 isoform (3.7 kb in human) is polyadenylated, 23 whereas the longer 23 kb subtype of Neat1_2 is not polyadenylated.…”

“… 19 There are two subtypes of mono-exonic isoforms transcribed from the Neat1 locus from chromosome 11, known as shorter Neat1_1 with 3684 nucleotides and longer Neat1_2 with 22,743 nucleotides. 19 , 44 The shorter Neat1_1 isoform (3.7 kb in human) is polyadenylated, 23 whereas the longer 23 kb subtype of Neat1_2 is not polyadenylated. Neat1_1 is high abundance and exhibits a high expression in a wide range of tissues.…”

“… 50 Similarly, the upregulation of Neat1 has a detrimental effect and accelerates disease progression in PD via regulating inflammation. 19 Moreover, the knockdown of Neat1 could inhibit microglia polarization towards the M1 phenotype in various neurological disorders. 62 Nevertheless, concerning the differences between diseases (dosage and delivery time), the studies used heterogeneous experimental paradigms meeting their own applied study purposes.…”

“…8,9 Nuclear paraspeckle assembly transcript 1 (Neat1), a nuclear lncRNAs, a vital component of paraspeckles, plays critical roles in multiple cellular physiology and pathophysiology, 10,11 such as the innate immune reaction, 12 organ development, 13,14 cancer [15][16][17] and neurodegenerative diseases. [18][19][20][21] There are two isoform transcripts of Neat1, Neat1_1 (3.7 kb) and Neat1_2 (23 kb), respectively, both of which are localized to nuclear paraspeckles. 22 Paraspeckles are a type of subnuclear body built on the Neat1 and enriched with various proteins, RNAs, which are involved in regulating gene expression by a process called nuclear retention.…”