Molecular Genetics of Frontotemporal Dementia Elucidated by Drosophila Models—Defects in Endosomal–Lysosomal Pathway

Abstract

Frontotemporal dementia (FTD) is the second most common senile neurodegenerative disease. FTD is a heterogeneous disease that can be classified into several subtypes. A mutation in CHMP2B locus (CHMP2Bintron5), which encodes a component of endosomal sorting complex required for transport-III (ESCRT-III), is associated with a rare hereditary subtype of FTD linked to chromosome 3 (FTD-3). ESCRT is involved in critical cellular processes such as multivesicular body (MVB) formation during endosomal–lysosomal pathway and autophagy. ESCRT mutants causes diverse physiological defects primarily due to accumulation of endosomes and defective MVBs resulting in misregulation of signaling pathways. Charged multivesicular body protein 2B (CHMP2B) is important for neuronal physiology which especially rely on precise regulation of protein homeostasis due to their post-mitotic status. Drosophila has proven to be an excellent model for charaterization of mechanistic underpinning of neurodegenerative disorders including FTD. In this review, current understanding of various FTD-related mutations is discussed with a focus on Drosophila models of CHMP2Bintron5-associated FTD.

A novel splice‐site mutation in CHMP2B associated with frontotemporal dementia: The first report from China and literature review

“…The CHMP2B protein consists of 213 amino acids, containing predicted coiled‐coil, Snf‐7, and acidic C‐terminal domains (Alqabandi et al, 2021 ; Krasniak & Ahmad, 2016 ). The normal structure participates in the conversion of CHMP2B proteins in both activation and quiescence, which permits them to polymerize into heterotypic ESCRT‐III complexes on the endosomal membrane (Alqabandi et al, 2021 ; Vandal et al, 2018 ).…”

“…It is characterized by distinct changes in behavior, language, and motor function (Greaves & Rohrer, 2019 ). About 30% of patients have a strong family history and most mutations associated with the FTD families occur in chromosome 9 open reading frame 72 ( C9orf72 ), progranulin ( GRN ), and microtubule‐associated protein tau (MAPT ) genes (Vandal et al, 2018 ) (AD&FTD Mutation database: http://www.molgen.ua.ac.be/FTDmutations ). Furthermore, mutations in the valosin‐containing protein ( VCP ) (Scarian et al, 2022 ), charged multivesicular body protein 2B ( CHMP2B ), transactive response DNA binding protein ( TARDBP ) (Synofzik et al, 2014 ), FUS RNA binding protein ( FUS ) (Oyston et al, 2021 ), and TANK binding kinase1 ( TBK1 ) (Pottier et al, 2015 ) genes are rare causes of familial FTD.…”

Modeling Neurodegenerative Disorders in Drosophila melanogaster

“…It often has an early onset. Genes that contribute to FTD include: C9ORF72, FUS, VCP, TDP-43, MAPT/tau, CHMP2B, PGRN, TBK1, and TMEM106B (reviewed in [95]), thus there is overlap with other neurodegenerative diseases including: ALS (C9ORF72, FUS, VCP and TDP-43), AD (tau) and PD (tau). C9ORF72, FUS, VCP, and TDP-43 studies in Drosophila are included in Table 3, while tau studies are listed in Tables 1 and 2.…”

Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

“…CHMP2B is a component of the endosomal sorting complex required for transport III (ESCRT-III) complex, which is involved in the maturation of endosomes and autophagosomes. Using cellular and animal models, mutations in CHMP2B (both truncated and missense mutations) have been shown to disrupt endosomal-lysosomal trafficking, through accumulation and enlargement of endosomes (Cox et al, 2010;Zhang Y. et al, 2017;Vandal et al, 2018). The pathology of FTD-3 cases is distinguished by the presence of ubiquitin and p62 (SQSTM1; FTDALS3) positive inclusions, which are negative for TDP-43 and Tau (Holm et al, 2007).…”