Jacek Jawors­ki

Lessons from mod­el­ing mTORopathies

Abstract

mTORopathies are mul­ti­or­gan dis­eases that result from exces­sive mTOR kinase activ­i­ty. Com­mon char­ac­ter­is­tics of mTORopathies include devel­op­men­tal alter­ations in the cere­bral cor­tex anato­my and the pres­ence of benign brain tumors. Clin­i­cal­ly, mTORopathies often present as epilep­sy, autism spec­trum dis­or­ders, and neu­ropsy­chi­atric dis­or­ders. One exten­sive­ly stud­ied mTORopa­thy is tuber­ous scle­ro­sis com­plex (TSC), which occurs due to the loss of func­tion of TSC1 or TSC2 pro­teins, both of which inhib­it mTOR. mTOR is a kinase whose activ­i­ty is reg­u­lat­ed by troph­ic fac­tors, ener­gy lev­els, and amino acid lev­els with­in the cell. 

In TSC, this reg­u­la­tion is dis­rupt­ed, lead­ing to dereg­u­la­tion of numer­ous mTOR-depen­dent process­es such as trans­la­tion, lipid and nucleotide biosyn­the­sis, autophagy, and tran­scrip­tion. Cur­rent­ly, patients with TSC receive symp­to­matic treat­ment, such as the admin­is­tra­tion of antiepilep­tic drugs or mTOR inhibitors like rapamycin. 

How­ev­er, there is still a need for new drugs, par­tic­u­lar­ly for TSC-asso­ci­at­ed neu­ropsy­chi­atric dis­or­ders. In our research, we employ a com­bi­na­tion of cel­lu­lar mod­els (such as in vit­ro neu­ron cul­tures, cells from tumor patients, and induced pluripo­tent stem cells from patients) and ani­mal mod­els (such as zebrafish and mice) to gain a bet­ter under­stand­ing of the mol­e­c­u­lar aspects of neu­rode­vel­op­ment in con­di­tions of mTOR over­ac­tiv­i­ty and to iden­ti­fy new ther­a­peu­tic tar­gets. This pre­sen­ta­tion will pro­vide an overview of our team’s research in these two areas.

Biog­ra­phy

Jacek Jawors­ki is a pro­fes­sor and the Deputy Direc­tor for Sci­ence at the Inter­na­tion­al Insti­tute of Mol­e­c­u­lar and Cell Biol­o­gy in War­saw, where he leads the Lab­o­ra­to­ry of Mol­e­c­u­lar and Cel­lu­lar Neu­ro­bi­ol­o­gy. He began his career at the Nenc­ki Insti­tute of Exper­i­men­tal Biol­o­gy, where he com­plet­ed his Ph.D. in 2001 under the super­vi­sion of Prof. Leszek Kacz­marek. Dur­ing his time in Prof. Kacz­marek’s lab, his research focused on inves­ti­gat­ing the role of tran­scrip­tion fac­tors in neu­ronal cell death.

Sub­se­quent­ly, he joined the Picow­er Insti­tute for Learn­ing and Mem­o­ry at MIT, where he stud­ied the mol­e­c­u­lar mech­a­nisms under­ly­ing neu­ronal devel­op­ment and neu­ronal struc­tur­al plas­tic­i­ty. One of his sig­nif­i­cant con­tri­bu­tions dur­ing this peri­od was the first demon­stra­tion of the involve­ment of the mTOR kinase in neu­ronal devel­op­ment. Since join­ing the IIM­CB, Prof. Jaworski’s research team has been ded­i­cat­ed to unrav­el­ing the mol­e­c­u­lar mech­a­nisms respon­si­ble for prop­er neu­ronal mor­phol­o­gy, with a spe­cif­ic empha­sis on mTOR-reg­u­lat­ed cel­lu­lar processes. 

In his recent work, Prof. Jawors­ki col­lab­o­rates with a net­work of Euro­pean researchers to inves­ti­gate how these process­es con­tribute to neu­rode­vel­op­men­tal patholo­gies such as epilep­sy and tuber­ous scle­ro­sis. In addi­tion to his dis­cov­ery of mTOR’s role in neu­ronal func­tion, Prof. Jawors­ki has also made sig­nif­i­cant con­tri­bu­tions in col­lab­o­ra­tion with Prof. Casper Hoogen­raad from Utrecht Uni­ver­si­ty. Togeth­er, they described for the first time the involve­ment of micro­tubule plus-end bind­ing pro­teins in den­drit­ic tree for­ma­tion and struc­tur­al synap­tic plas­tic­i­ty in neurons. 

The research con­duct­ed by Prof. Jawors­ki and his team has been pub­lished in sev­er­al pres­ti­gious peer-reviewed jour­nals, includ­ing Neu­ron, PNAS, EMBO J., and J. Neu­rosci. This year, he was elect­ed as a mem­ber of the Euro­pean Mol­e­c­u­lar Biol­o­gy Organization.