A lncRNA survey finds increases in neuroprotective LINC-PINT in Parkinson's disease substantia nigra.

Alon Simchovitz,Mor Hanan,Sebastian Kadener,Hermona Soreq,David S Greenberg,Songhua Lee,Estelle R Bennett,Nadav Yayon

doi:10.1111/acel.13115

Abstract

Recent reports highlight regulatory functions of long noncoding RNAs (lncRNAs) in neurodegeneration and aging, but biomedical implications remain limited. Here, we report an rRNA‐depletion‐based long RNA‐Sequencing Resource of 65 substantia nigra, amygdala, and medial temporal gyrus samples from Parkinson's disease (PD) and matched control brains. Using a lncRNA‐focused analysis approach to identify functionally important transcripts, we discovered and prioritized many lncRNAs dysregulated in PD. Those included pronounced elevation of the P53‐induced noncoding transcript LINC‐PINT in the substantia nigra of PD patients, as well as in additional models of oxidative stress and PD. Intriguingly, we found that LINC‐PINT is a primarily neuronal transcript which showed conspicuous increases in maturing primary culture neurons. LINC‐PINT also accumulated in several brain regions of Alzheimer's and Huntington's disease patients and decreased with healthy brain aging, suggesting a general role in aging and neurodegeneration for this lncRNA. RNAi‐mediated depletion of LINC‐PINT exacerbated the death of cultured N2A and SH‐SY5Y cells exposed to oxidative stress, highlighting a previously undiscovered neuroprotective role for this tumor‐inducible lncRNA in the brains of patients with neurodegenerative disorders.

Highlights

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting approximately 2% of adults over the age of 70 worldwide (Pringsheim, Jette, Frolkis, & Steeves, 2014)
One class of RNAs with unclear role in PD initiation and progression includes long noncoding RNAs, which are a diverse subset of transcripts longer than 200 nucleotides that do not encode for proteins
The three differentially expressed (DE) transcripts which exhibited the most significant decrease in the substantia nigra (SN) of PD patients in our dataset were syndecan-4 (SDC4), calcium/calmodulin-dependent protein kinase IV (CAMK4), and early growth response 1 (EGR1). To test whether this decrease could be mediated by LINC-PINT, we modeled its neuronal knockdown by administering LINC-PINT-targeted GapmeRs (Qiagen) to the human neuroblastoma cell line SH-SY5Y

Summary

| INTRODUCTION

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting approximately 2% of adults over the age of 70 worldwide (Pringsheim, Jette, Frolkis, & Steeves, 2014). To seek correlations between the expression patterns of those top-scoring lncRNAs in different brain regions, we examined a subset of 13 donors for whom all three examined brain regions were available (39 libraries overall), and identified only a single statistically significant correlation, between RMST expression levels in the SN and MTG (Figure 3d) This further marked the importance of investigating the transcriptional landscape of the SN. Likewise, interrogating a WAD of RNA-Seq of the striatum of mice exposed to PQ (GSE36232) (Gollamudi et al, 2012) revealed a 5.5-fold increase in Lncpint levels in the exposed mice (Figure S6), demonstrating parallel effects of oxidative stress at the tissue level This indicated functional involvement of both LINC-PINT and its murine homolog in neuronal oxidative stress responses. LINC-PINT’s accumulation under exposure to oxidative stress could potentially reflect a reaction which attenuates disease

| DISCUSSION

Findings

| MATERIALS AND METHODS