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

Sarah Vandal,S Ahmad,Xiaoyue Zheng

doi:10.3390/ijms19061714

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.

Highlights

Frontotemporal dementia (FTD) is the second most common form of dementia, and the second most common neurodegenerative disease in individuals under the age of 65 [1]
One subtype is the behavioral variant of FTD, which is typically classified by gradual changes in behavior, cognition, or both
This disorder is further divided into additional subgroups which are categorized based on a spectrum of the areas of language affected: logopenic variant progressive aphasia (PPA), nonfluent variant PPA, and semantic dementia (SD) [2,3,4]

Summary

Introduction

Frontotemporal dementia (FTD) is the second most common form of dementia, and the second most common neurodegenerative disease in individuals under the age of 65 [1] It is characterized by progressive impairment of language and executive functioning, as well as behavioral modifications, due to degeneration of the frontal and temporal lobes of the brain [2,3]. Sci. 2018, 19, x FOR PEER REVIEW display cogAnnitiavdediitmiopnaalirsmubetynpt,esoofcFiaTlDb, echalalevdiofrrodnetofitcemitsp,oarnaldddemysetnotinaiali,nwkehdictohcthyrpoimcaolsloymaep3p(eFaTrDb-etween the age3s),oifs4d6oamnidna6n7tly[1i]n.hFeorirtetdhiasnrdeaissocnh,arFaTctDer-i3zeids cblyassseilfiecetdivue ncdoretrictahl eneFuTrDonsduebgteynpeeraotifonfr.oFnTtDot-e3mporal lobar dpematieennttsiad[is5p].laOy ncoegonfittihvee igmepnaeitrimc ednetf, escotcsiaalsbseohcaivaitoerddwefiictihtsF, aTnDd-d3yisstoanmiau, wtahtiicohntyinpitchaellyCaHpMpePar2B gene; between the ages of 46 and 67 [1] For this reason, FTD-3 is classified under the FTD subtype of atwsionagbleftnhronoenruCtmcoHltaeeMlmoPttpri2daoBrneagslmeclnorueibp;taaatrtsdsi,oienCnmgHl(eeGnMntiutPaoc2[l5CeB]o.i)tnOiatdrntoenet5mhoeafunttshadpteilogCinceHen(eGMstiittcPoed2oCeBff)e∆Cac1tt0Hst,haMbessosoPtpch2liiaBcoteeefdsxwiwotehnitoihc6f h.FCTTHeDhnM-ic3sPoiv2dsBaearemifxaooutrnitoap6tnri.ooTentsheitiniasnbsliwshitehs a defecvtiavrieatciaornbeosxtaybllitsehrems tiwnousab[n5o–r7m].al transcripts, CHMP2Bintron and CHMP2BΔ10, both of which encode. Transmembrane protein 106B (TMEM106B), contribute in the development of the endosome and MVB pathway in the endosomal–lysosomal pathway

Mutations Associated with FTD

Structure and Function of CHMP2B

Defects Caused by CHMP2Bintron5

Future Perspectives

Findings

Conclusions