An Alzheimer's Disease-Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation, Consistent with a Retromer Trafficking Defect

Yasir H Qureshi; Vivek M Patel; Diego E Berman; Milankumar J Kothiya; Jessica L Neufeld; Badri Vardarajan; Min Tang; Dolly Reyes-Dumeyer; Rafael Lantigua; Martin Medrano; Ivonne J Jiménez-Velázquez; Scott A Small; Christiane Reitz

doi:10.1128/MCB.00011-18

An Alzheimer's Disease-Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation, Consistent with a Retromer Trafficking Defect

Mol Cell Biol. 2018 Sep 28;38(20):e00011-18. doi: 10.1128/MCB.00011-18. Print 2018 Oct 15.

Authors

Yasir H Qureshi¹, Vivek M Patel¹, Diego E Berman^{1

2}, Milankumar J Kothiya¹, Jessica L Neufeld¹, Badri Vardarajan^{1

3}, Min Tang^{1

3}, Dolly Reyes-Dumeyer¹, Rafael Lantigua⁴, Martin Medrano⁵, Ivonne J Jiménez-Velázquez⁶, Scott A Small^{7

8

2}, Christiane Reitz^{7

3

8

9}

Affiliations

¹ The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA.
² Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
³ The Gertrude H. Sergievsky Center, Columbia University, New York, New York, USA.
⁴ Department of Medicine, Columbia University, New York, New York, USA.
⁵ School of Medicine, Pontificia Universidad Catolica Madre y Maestra, Santiago, Dominican Republic.
⁶ Department of Internal Medicine, University of Puerto Rico School of Medicine, San Juan, Puerto Rico.
⁷ The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA [email protected] [email protected].
⁸ Department of Neurology, Columbia University, New York, New York, USA.
⁹ Department of Epidemiology, Columbia University, New York, New York, USA.

Abstract

In a whole-exome sequencing study of multiplex Alzheimer's disease (AD) families, we investigated three neuronal ceroid lipofuscinosis genes that have been linked to retromer, an intracellular trafficking pathway associated with AD: ceroid lipofuscinosis 3 (CLN3), ceroid lipofuscinosis 5 (CLN5), and cathepsin D (CTSD). We identified a missense variant in CLN5 c.A959G (p.Asn320Ser) that segregated with AD. We find that this variant causes glycosylation defects in the expressed protein, which causes it to be retained in the endoplasmic reticulum with reduced delivery to the endolysosomal compartment, CLN5's normal cellular location. The AD-associated CLN5 variant is shown here to reduce the normal processing of cathepsin D and to decrease levels of full-length amyloid precursor protein (APP), suggestive of a defect in retromer-dependent trafficking.

Keywords: Alzheimer's disease; CLN5; NCL; endosomes; retromer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / genetics*
Alzheimer Disease / metabolism*
Amino Acid Sequence
Amyloid beta-Protein Precursor / metabolism
Cathepsin D / metabolism*
Endoplasmic Reticulum / metabolism
Endosomes / metabolism
Exome Sequencing
Glycosylation
HeLa Cells
Humans
Loss of Function Mutation*
Lysosomal Membrane Proteins
Lysosomes / metabolism
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism
Membrane Proteins / genetics*
Membrane Proteins / metabolism*
Molecular Chaperones / genetics
Molecular Chaperones / metabolism
Mutation, Missense
Neuronal Ceroid-Lipofuscinoses / genetics*
Neuronal Ceroid-Lipofuscinoses / metabolism*
Protein Processing, Post-Translational
Protein Transport
Sequence Homology, Amino Acid

Substances

Amyloid beta-Protein Precursor
CLN3 protein, human
CLN5 protein, human
Lysosomal Membrane Proteins
Membrane Glycoproteins
Membrane Proteins
Molecular Chaperones
CTSD protein, human
Cathepsin D

Supplementary concepts

Ceroid lipofuscinosis, neuronal 5

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding