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, 3 (4), 243-252

NEAT1 and Paraspeckles in Neurodegenerative Diseases: A Missing Lnc Found?


NEAT1 and Paraspeckles in Neurodegenerative Diseases: A Missing Lnc Found?

Haiyan An et al. Noncoding RNA Res.


Neurodegenerative diseases are among the most common causes of disability worldwide. Although neurodegenerative diseases are heterogeneous in both their clinical features and the underlying physiology, they are all characterised by progressive loss of specific neuronal populations. Recent experimental evidence suggests that long non-coding RNAs (lncRNAs) play important roles in the CNS in health and disease. Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) is an abundant, ubiquitously expressed lncRNA, which forms a scaffold for a specific RNA granule in the nucleus, or nuclear body, the paraspeckle. Paraspeckles act as molecular hubs for cellular processes commonly affected by neurodegeneration. Transcriptomic analyses of the diseased human tissue have revealed altered NEAT1 levels in the CNS in major neurodegenerative disorders as well as in some disease models. Although it is clear that changes in NEAT1 expression (and in some cases, paraspeckle assembly) accompany neuronal damage, our understanding of NEAT1 contribution to the disease pathogenesis is still rudimentary. In this review, we have summarised the available knowledge on NEAT1 involvement in the molecular processes linked to neurodegeneration and on NEAT1 dysregulation in this type of disease, with a special focus on amyotrophic lateral sclerosis. The goal of this review is to attract the attention of researchers in the field of neurodegeneration to NEAT1 and paraspeckles.

Keywords: Amyotrophic lateral sclerosis; NEAT1; Neurodegeneration; Paraspeckle; lncRNA.


Fig. 1
Fig. 1
NEAT1/paraspeckles in ALS: a working model. Left panel. Under basal conditions, levels of NEAT1_2 in motor neurons are low and so are the paraspeckle numbers. Paraspeckle assembly might also be transient (“on demand”). Middle panel. During development of pathological changes typical for ALS, paraspeckle hyper-assembly is triggered by internal and external insults, such as TDP-43 loss of function (LoF), proteostasis collapse and immune response. Subsequent signalling events would enable protective neuronal response to stress and delay neuronal degeneration. Right panel. In ALS cases with an essential/important paraspeckle protein affected by a mutation (see Table 2), its mutant isoform might negatively impact on protective paraspeckle hyper-assembly. This can be realised through: i) failure to upregulate NEAT1_2 (e.g. if proteins regulating NEAT1_2 levels, such as SFPQ and hnRNP K, are mutated or sequestered into abnormal inclusions/RNA foci); ii) attenuated assembly of paraspeckles or assembly of dysfunctional paraspeckles (e.g. if a structural paraspeckle protein, such as FUS, is mutated); iii) persistence of paraspeckles (e.g. if a mutation confers abnormal stability). Defective paraspeckle response may expedite the development of molecular pathology and accelerate disease onset and progression. A mutant protein is marked by a red star.

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