The Molecular Function of PURA and Its Implications in Neurological Diseases

Abstract

In recent years, genome-wide analyses of patients have resulted in the identification of a number of neurodevelopmental disorders. Several of them are caused by mutations in genes that encode for RNA-binding proteins. One of these genes is PURA, for which in 2014 mutations have been shown to cause the neurodevelopmental disorder PURA syndrome. Besides intellectual disability (ID), patients develop a variety of symptoms, including hypotonia, metabolic abnormalities as well as epileptic seizures. This review aims to provide a comprehensive assessment of research of the last 30 years on PURA and its recently discovered involvement in neuropathological abnormalities. Being a DNA- and RNA-binding protein, PURA has been implicated in transcriptional control as well as in cytoplasmic RNA localization. Molecular interactions are described and rated according to their validation state as physiological targets. This information will be put into perspective with available structural and biophysical insights on PURA’s molecular functions. Two different knock-out mouse models have been reported with partially contradicting observations. They are compared and put into context with cell biological observations and patient-derived information. In addition to PURA syndrome, the PURA protein has been found in pathological, RNA-containing foci of patients with the RNA-repeat expansion diseases such as fragile X-associated tremor ataxia syndrome (FXTAS) and amyotrophic lateral sclerosis (ALS)/fronto-temporal dementia (FTD) spectrum disorder. We discuss the potential role of PURA in these neurodegenerative disorders and existing evidence that PURA might act as a neuroprotective factor. In summary, this review aims at informing researchers as well as clinicians on our current knowledge of PURA’s molecular and cellular functions as well as its implications in very different neuronal disorders.

Depletion of the RNA-binding protein PURA triggers changes in posttranscriptional gene regulation and loss of P-bodies

“…Consistent with a nuclear role of PURA, we do observe binding of PURA to nuclear RNAs such as NEAT1 and MALAT1 . The minor fraction of PURA in the nucleus might be involved in transcriptional regulation as reported previously (3,15). While this might be one of PURAs functions, it was subsequently shown to associate with cellular RNAs and to bind single-stranded DNA and RNA sequences in vitro in the same way and with similar affinities (23).…”

“…In recent years, an increasing number of RNA-binding proteins have been implicated in the pathology of human disorders, in particular in neuronal diseases (1,2). One of them is the purine rich element binding protein A (PURA, formerly known as Puralpha) (3). In 2014, mutations in the PURA gene have been linked to the neurodevelopmental disorder PURA Syndrome (4,5).…”

Liquid-Liquid Phase Separation of TDP-43 and FUS in Physiology and Pathology of Neurodegenerative Diseases

“…For example, deletions of the PURA gene cause PURA syndrome, a neurodevelopmental disorder. There is also evidence demonstrating Pur-alpha can associate with RNAs including NEAT1 and C9orf72 repeat expansions, and it can be incorporated into stress granules [further reviewed in (Molitor et al, 2021)]. Recently, Daigle et al identified Pur-alpha in stress granules derived from FUS-ALS patients and, upon shRNA-mediated knockdown in HEK293T cells, prevented stress granule formation, suggesting Pur-alpha may be able to regulate FUS LLPS (Daigle et al, 2016).…”

Structural Protein Effects Underpinning Cognitive Developmental Delay of the PURA p.Phe233del Mutation Modelled by Artificial Intelligence and the Hybrid Quantum Mechanics–Molecular Mechanics Framework

“…Evolution has tagged this genomic region as inalterable, which may prove its unique and essential role in interacting with DNA and RNA molecules. It has been reported that any mutation in the PURA protein causes the full spectrum of the human PURA syndrome [ 53 ].…”