Moni­ka Myszczyńska

Modelling non-cell autonomous mechanisms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in vitro

Mod­el­ling non-cell autonomous mech­a­nisms of amy­otroph­ic lat­er­al scle­ro­sis (ALS) and fron­totem­po­ral demen­tia (FTD) in vit­ro

Abstract

Amy­otroph­ic lat­er­al scle­ro­sis (ALS) is a fatal neu­rode­gen­er­a­tive dis­or­der char­ac­terised by motor neu­ron (MN) death. ALS is pre­dom­i­nant­ly spo­radic in ori­gin, with only 10% of cas­es pre­sent­ing a clear genet­ic cause. Of the dif­fer­ent genet­ic muta­tions asso­ci­at­ed with ALS, a hexa­nu­cleotide repeat expan­sion in the C9orf72 gene rep­re­sents the largest pro­por­tion of famil­ial ALS patients. Regard­less of the causative ori­gin of ALS, 97% of all patients show mis­lo­cal­i­sa­tion of a key DNA and RNA-bind­ing pro­tein called TDP-43. TDP-43 and C9orf72 muta­tions, amongst oth­ers, are also present in fron­totem­po­ral demen­tia (FTD), thus putting ALS and FTD on a genet­ic spectrum.

Although MNs are the cells pri­mar­i­ly affect­ed, astro­cytes and oth­er glial cells have been shown to play a role in the dis­ease. iAs­tro­cytes show hall­marks of C9orf72 muta­tion, includ­ing a pres­ence of nuclear RNA foci and cyto­plas­mic dipep­tide repeat pro­teins, as well as TDP-43 pro­teinopa­thy. To study the non-cell autonomous mech­a­nism of ALS, we have set up co-cul­tures of induced astro­cytes (iAs­tro­cytes) dif­fer­en­ti­at­ed from neur­al prog­en­i­tor cells (iNPCs), repro­grammed direct­ly from patient fibrob­lasts, and motor neu­rons derived from induced pluripo­tent stem cell (iPSC). Patho­phys­i­o­log­i­cal­ly-rel­e­vant assays where astro­cytes and neu­rons are co-cul­tured, reca­pit­u­late the astro­cyte tox­i­c­i­ty against neu­rons in both ALS and FTD cas­es, and can be used to screen drug candidates.

Biog­ra­phy

Dr. Moni­ka Myszczyn­s­ka is a post­doc­tor­al research asso­ciate at the Uni­ver­si­ty of Sheffield, based at the Sheffield Insti­tute for Trans­la­tion­al Neu­ro­science (SITraN). She stud­ies the non-cell autonomous mech­a­nism of motor neu­ron dis­ease (MND), focus­ing on the role of astro­cytes in the dis­ease. She spe­cial­izes in in vit­ro dis­ease mod­el­ling and uti­lizes the mod­els to unrav­el the mechanism(s) of action of drug can­di­dates to treat MND.