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TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 10-6). Postmortem neuropathology of five TIA1 mutations carriers showed a consistent pathological signature with numerous round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive inclusions. TIA1 mutations significantly increased the propensity of TIA1 protein to undergo phase transition. In live cells, TIA1 mutations delayed stress granule (SG) disassembly and promoted the accumulation of non-dynamic SGs that harbored TDP-43. Moreover, TDP-43 in SGs became less mobile and insoluble. The identification of TIA1 mutations in ALS/FTD reinforces the importance of RNA metabolism and SG dynamics in ALS/FTD pathogenesis.

SUBMITTER: Mackenzie IR

PROVIDER: S-EPMC5576574 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Mackenzie Ian R IR Nicholson Alexandra M AM Sarkar Mohona M Messing James J Purice Maria D MD Pottier Cyril C Annu Kavya K Baker Matt M Perkerson Ralph B RB Kurti Aishe A Matchett Billie J BJ Mittag Tanja T Temirov Jamshid J Hsiung Ging-Yuek R GR Krieger Charles C Murray Melissa E ME Kato Masato M Fryer John D JD Petrucelli Leonard L Zinman Lorne L Weintraub Sandra S Mesulam Marsel M Keith Julia J Zivkovic Sasha A SA Hirsch-Reinshagen Veronica V Roos Raymond P RP Züchner Stephan S Graff-Radford Neill R NR Petersen Ronald C RC Caselli Richard J RJ Wszolek Zbigniew K ZK Finger Elizabeth E Lippa Carol C Lacomis David D Stewart Heather H Dickson Dennis W DW Kim Hong Joo HJ Rogaeva Ekaterina E Bigio Eileen E Boylan Kevin B KB Taylor J Paul JP Rademakers Rosa R

Neuron 20170801 4

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 10<su ...[more]

PMID: 28817800

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Project description:Amyotrophic lateral sclerosis and frontotemporal dementia are two progressive, adult onset neurodegenerative diseases, caused by the cell death of motor neurons in the motor cortex and spinal cord and cortical neurons in the frontal and temporal lobes, respectively. Whilst these have previously appeared to be quite distinct disorders, in terms of areas affected and clinical symptoms, identification of cognitive dysfunction as a component of amyotrophic lateral sclerosis (ALS), with some patients presenting with both ALS and FTD, overlapping features of neuropathology and the ongoing discoveries that a significant proportion of the genes underlying the familial forms of the disease are the same, has led to ALS and FTD being described as a disease spectrum. Many of these genes encode proteins in common biological pathways including RNA processing, autophagy, ubiquitin proteasome system, unfolded protein response and intracellular trafficking. This article provides an overview of the ALS-FTD genes before summarizing other known ALS and FTD causing genes where mutations have been found primarily in patients of one disease and rarely in the other. In discussing these genes, the review highlights the similarity of biological pathways in which the encoded proteins function and the interactions that occur between these proteins, whilst recognizing the distinctions of MAPT-related FTD and SOD1-related ALS. However, mutations in all of these genes result in similar pathology including protein aggregation and neuroinflammation, highlighting that multiple different mechanisms lead to common downstream effects and neuronal loss. Next generation sequencing has had a significant impact on the identification of genes associated with both diseases, and has also highlighted the widening clinical phenotypes associated with variants in these ALS and FTD genes. It is hoped that the large sequencing initiatives currently underway in ALS and FTD will begin to uncover why different diseases are associated with mutations within a single gene, especially as a personalized medicine approach to therapy, based on a patient's genetics, approaches the clinic.

Dataset Information

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Publications

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

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