The role of lysosomes and autophagosomes in Frontotemporal Lobar Degeneration

Research output: Contribution to journalArticle

  • External authors:
  • Hamish Dc Bain
  • Yvonne S Davidson
  • Anna Richardson
  • Matthew Jones
  • Julie S Snowden
  • David M A Mann

Abstract

INTRODUCTION: Cell biological and genetic evidence implicates failures in degrading aggregating proteins, such as tau and TDP-43, through autophagy or lysosomal pathways in the pathogenesis of Frontotemporal Lobar degeneration (FTLD).

METHODS: We investigated changes in degradative pathways in 60 patients with different pathological or genetic forms of FTLD employing immunohistochemistry for marker proteins such as Lysosomal Associated Membrane Proteins 1 (LAMP-1) and 2 (LAMP-2), Cathepsin D (CTSD) and microtubule-associated protein 1 light chain 3 alpha (LC3A). Immunostained sections were qualitatively and semi-quantitatively assessed for the appearance, distribution and intensity of staining in neurones of dentate gyrus (DG) and CA4 region of hippocampus, and temporal cortex (Tcx).

RESULTS: Lower levels of neuronal LAMP-1 immunostaining were present in DG and Tcx in FTLD-tau compared to FTLD-TDP. There was less LAMP-1 immunostaining in FTLD-tau with MAPT mutations, and FTLD-tau with Pick bodies, compared to FTLD-TDP types A and B, and less LAMP-1 immunostaining in FTLD-TDP type C than in FTLD-TDP types A and B. There was greater LAMP-1 immunostaining in GRN mutation which may reflect the underlying type A histology rather than mutation. There were no differences in neuronal LAMP-2, CTSD, EEA-1 or LC3A immunostaining between any of the 5 FTLD histological or 4 genetic groups, nor between FTLD-TDP and FTLD-tau.

CONCLUSIONS: The underlying pathological mechanism in FTLD-tau may lie with a relative deficiency of lysosomes, or defective vesicular transport, whereas the failure to clear TDP-43 aggregates may lie with lysosomal dysfunction rather than a lack of available lysosomes or degradative enzymes. This article is protected by copyright. All rights reserved.

Bibliographical metadata

Original languageEnglish
JournalNeuropathology and Applied Neurobiology
Early online date23 May 2018
DOIs
Publication statusPublished - 2018