Altered localization and functionality of TAR DNA Binding Protein 43 (TDP-43) in niemann- pick disease type C.

A Dardis,C Stuani,K L Newell,B Bembi,E Buratti,J R Murrell,M T Fiorenza,B Ghetti,S Zampieri,S Canterini

doi:10.1186/s40478-016-0325-4

Abstract

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by the occurrence of visceral and neurological symptoms. At present, the molecular mechanisms causing neurodegeneration in this disease are unknown. Here we report the altered expression and/or mislocalization of the TAR-DNA binding protein 43 (TDP-43) in both NPC mouse and in a human neuronal model of the disease. We also report the neuropathologic study of a NPC patient’s brain, showing that while TDP-43 is below immunohistochemical detection in nuclei of cerebellar Purkinje cells, it has a predominant localization in the cytoplasm of these cells. From a functional point of view, the TDP-43 mislocalization, that occurs in a human experimental neuronal model system, is associated with specific alterations in TDP-43 controlled genes. Most interestingly, treatment with N-Acetyl-cysteine (NAC) or beta-cyclodextrin (CD) can partially restore TDP-43 nuclear localization. Taken together, the results of these studies extend the role of TDP-43 beyond the Amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)/Alzheimer disease (AD) spectrum. These findings may open novel research/therapeutic avenues for a better understanding of both NPC disease and the TDP-43 proteinopathy disease mechanism.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0325-4) contains supplementary material, which is available to authorized users.

Highlights

Niemann-Pick disease, type C [Niemann-Pick type C (NPC)-MIM 257220; MIM607625] is an autosomal recessive lysosomal storage disorder due to mutations in NPC1 (95 % of patients) or NPC2 genes, encoding two proteins involved in the intracellular trafficking of cholesterol and other lipids
The expression of TAR-DNA binding protein 43 (TDP-43) appeared significantly reduced in the cerebellum of Npc1−/− mice as early as postnatal (PN) day 11, when neuropathological features of the disease had not yet appeared
Proliferating granule neurons (GN) localize in the outer part of the external granular layer whereas postmitotic GNs stop in the inner part of the EGL before migrating inward through the molecular layer (ML) to reach the internal granular layer (IGL), representing the migrating GNs

Summary

Introduction

Niemann-Pick disease, type C [NPC-MIM 257220; MIM607625] is an autosomal recessive lysosomal storage disorder due to mutations in NPC1 (95 % of patients) or NPC2 genes, encoding two proteins involved in the intracellular trafficking of cholesterol and other lipids. The deficiency of either protein leads to the accumulation of endocytosed unesterified cholesterol, gangliosides, and other lipids within the lysosome/late endosome compartment [1]. The clinical presentation of the disease is variable, and the age at onset ranges from the perinatal period to adulthood. The disease is typically characterized by visceral and neurological symptoms. Neuropathological features include meganeurite formation, extensive growth of ectopic dendrites, formation of neurofibrillary tangles, neuroinflammation and neuroaxonal dystrophy [2]. The molecular events linking lysosomal storage and cellular damage are not well understood

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