Dr#Julia#Fitzgerald#

The#Role#of#TRAP1#in#Parkinson’s#disease####

Her$e%Ins$tute%for%Clinical%Brain%Research,%Tübingen,%Germany%

11th%Annual%GeoPD%Mee$ng.%Luxembourg,%7th%October%2016%

TRAP1%in%Mitochondrial%Quality%Control%

Julia%Fitzgerald%

Park%et%al.%2006%Clark%et%al.%2006%Narendra%et%al.%2008%Geisler%et%al%2010%Wang%et%al.%2011%Birsa%et%al.%2014%Et.%al....%%Bus#et#al.#In#prepara?on#

PlunUFavreau%et%al.%2007%Pridgeon%et%al.%2007%Costa%et%al.%2013%Zhang%et%al.%2013%%Fitzgerald#et#al.#In#prepara?on#

Kageyama%et%al.%2014%Pryde%et%al.%2016%

Proteostasis%QC%Oxida$ve%QC%Dynamics%QC%

Julia%Fitzgerald%

TRAP1%and%HtrA2%Interact%

Mass%spec%

Pull%down% Confirm%

Julia%Fitzgerald%

TRAP1%Rescues%HtrA2%Loss%of%Func$on%Phenotypes%

HtrA2#MEFs#

TRAP1#DNA#

Julia%Fitzgerald,%Kevin%Schindler%

TRAP1%is%not%Directly%Degraded%by%HtrA2%

o  Possibly%via%chaperone%func$on%of%TRAP1%or%HtrA2%o  TRAP1%could%bind%to%the%PDZ%domain%of%HtrA2%o  PDZ%detect%long%hydrophobic%stretches%at%CU

terminals.%

Basic%structure%of%HtrA2%

Julia%Fitzgerald,%Manu%Sharma,%Alex%Zimprich%

TRAP1%Muta$ons%in%PD%%

Julia%Fitzgerald%

Func$onal%Analaysis:%TRAP1%R47X%Muta$on%%

Julia%Fitzgerald%

TRAP1%R47X%Muta$on:%Mitochondrial%Physiology%%

Complex%I% ATP%

ΔmΨ% OCR%

Dr%Julia%Fitzgerald%

TRAP1%Regulates%Metabolic%Switching%

Julia%Fitzgerald%

TRAP1%Loss%of%Func$on%Phenotype%can%be%reversed%%

•  An$oxidant%(NAC)%has%no%effect%•  Mild%OXPHOS%inhibi$on%(Medormin%&%Oligo)%increases%mitochondrial%membrane%poten$al%

Julia%Fitzgerald%

Hypothesis%

Aging%&%Environment%

Metabolism,%Neurodegenera$on%

&%Risk%%

Gene%Muta$on%

• Redox%/%Reac$ve%oxygen%species%• Dopamine%• Calcium%and%pacemaking%• Mitochondrial%toxins%

• Energy,%longevity%• Iron%• Synapse%%health%• Aggrega$on%• Ancient,%common%varia$ons%with%small%effect%

• Gene%muta$ons%• Pathway%altered%• Compensa$on?%• Recent%rare%variants,%new%de%novo%with%large%reffect%%

Julia%Fitzgerald%

Relevance%of%TRAP1%in%PD%

•  Mitochondrial%pathways%to%PD%could%include%metabolism%as%well%as%mitophagy%•  Fine%control%of%mitochondrial%energy%metabolism%crucial%for%survival%of%neurons%•  Targe$ng%energy%metabolism%has%been%shown%to%%improve%diabetes,%cancer%and%PD%

Acknowledgements%

Her?e#Ins?tuteETübingen##########################

Rejko&Krüger&&Thomas&Gasser&&Kevin&Schindler&Chris?ne#Bus#

Lisa#Schwarz#

Manuela#Kuebler#

Katharina%Stegen%Richard%Wüst%%%University#of#Tübingen/DZNE#Tübingen#

Thomas%Oi%%Nicolas%Casadei%Peter#Heu?nk#

Ashutosh#Dhingra#Johannes%Glöckner%Craig%Mageean%Michael%Monaghan%Katja%Schenke%Leyland%%%

Université#du#Luxembourg#

Rejko&Krüger%Enrico%Glaab%Ibrahim%Boussaad%%%University%of%Vienna%Alexander#Zimprich#University%College%London%Andrey%Abramov%Iain%Hargreaves%Hélène%PlunUFavreau%University%of%Geneva%Didier#Picard#University%of%Leicester%(MRC)%Miguel#Mar?ns#

Aachen%University%Aaron%Voigt% %%%%

Dr%Julia%Fitzgerald%

Chris$ne%%Bus%

Manuela%Kübler%

Katharina%Stegen%

Kevin%Schindler%

Lisa%Schwarz%

Julia%Fitzgerald%

TRAP1%R47X%Muta$on:%Mitochondrial%Physiology%%

Complex%I% ATP%

ΔmΨ%

OCR%

MitoUnuclear%balance%