Investigating the Endo-Lysosomal System in Major Neurocognitive Disorders Due to Alzheimer's Disease, Frontotemporal Lobar Degeneration and Lewy Body Disease: Evidence for SORL1 as a Cross-Disease Gene.

Luisa Benussi,Sonia Bellini,Claudia Saraceno,Julie Van Der Zee,Giuliano Binetti,Roberta Ghidoni,Cemile Kocoglu,Giuseppe Di Fede,Silvia Fostinelli,Clarissa Ferrari,Roland Nicsanu,Antonio Longobardi,Matteo Carrara,Matthieu Moisse,Marcella Catania,Roberta Zanardini,Cristian Bonvicini,Christine Van Broeckhoven,Philip Van Damme

doi:10.3390/ijms222413633

Abstract

Dysfunctions in the endo-lysosomal system have been hypothesized to underlie neurodegeneration in major neurocognitive disorders due to Alzheimer’s disease (AD), Frontotemporal Lobar Degeneration (FTLD), and Lewy body disease (DLB). The aim of this study is to investigate whether these diseases share genetic variability in the endo-lysosomal pathway. In AD, DLB, and FTLD patients and in controls (948 subjects), we performed a targeted sequencing of the top 50 genes belonging to the endo-lysosomal pathway. Genetic analyses revealed (i) four previously reported disease-associated variants in the SORL1 (p.N1246K, p.N371T, p.D2065V) and DNAJC6 genes (p.M133L) in AD, FTLD, and DLB, extending the previous knowledge attesting SORL1 and DNAJC6 as AD- and PD-related genes, respectively; (ii) three predicted null variants in AD patients in the SORL1 (p.R985X in early onset familial AD, p.R1207X) and PPT1 (p.R48X in early onset familial AD) genes, where loss of function is a known disease mechanism. A single variant and gene burden analysis revealed some nominally significant results of potential interest for SORL1 and DNAJC6 genes. Our data highlight that genes controlling key endo-lysosomal processes (i.e., protein sorting/transport, clathrin-coated vesicle uncoating, lysosomal enzymatic activity regulation) might be involved in AD, FTLD and DLB pathogenesis, thus suggesting an etiological link behind these diseases.

Highlights

Major neurocognitive disorders due to Alzheimer’s disease (AD), FrontotemporalLobar Degeneration (FTLD), and Lewy body disease (DLB), are all characterized by abnormal protein accumulation [1,2]
Targeted genetic screening for the presence of variants in the coding regions of 50 candidate endo-lysosomal genes was performed on a total of n = 697 patients (n = 282 AD, n = 114 DLB, n = 301 Frontotemporal Lobar Degeneration (FTLD)) and n = 251 controls (Table 1)
We recently described that an alteration in the release of extracellular vesicle (EV) is common across AD, FTLD, and DLB and that plasma EV parameters (EV concentration/size) can distinguish patients from controls with strong sensitivity and specificity [21]

Summary

Introduction

Lobar Degeneration (FTLD), and Lewy body disease (DLB), are all characterized by abnormal protein accumulation [1,2]. AD is characterized by the deposition of beta-amyloid (Aβ) and phosphorylated tau peptides [3]. DLB, by alpha-synuclein deposits [4], and FTLD presents tau-, ubiquitin-, Fused-in-Sarcoma (FUS)-, and TAR DNA-binding protein. The pathogenesis of neurodegenerative disease was recently reviewed, describing AD as a mixed proteinopathy (amyloid and tau) frequently associated with other age-related co-pathologies, such as cerebrovascular lesions, Lewy and TDP-43 pathologies [6]. A specific subtype of extracellular vesicle (EV) of endosomal origin, have been suggested as potential carriers of misfolded toxic proteins: Aβ and tau in AD [8] and alpha-synuclein in Parkinson’s disease (PD)/DLB [9]

Objectives

Methods

Conclusion