Darius Ebrahimi-Fakhari

Darius Ebrahimi-Fakhari, MD, PhD

Assistant Professor of Neurology

Research Focus

Translational research in childhood-onset movement disorders

Brief Research Description

Dr. Ebrahimi-Fakhari’s research interests cover childhood-onset neurogenetic, neurodegenerative, and movement disorders. He leads a translational research program that aims to discover novel therapies for childhood-onset forms of hereditary spastic paraplegia and disorders related to the autophagy pathway. Current work covers gene discovery, natural history studies in patients, disease modeling in iPSC-derived neurons and zebrafish, and high-throughput small molecule screens and CRISPR screens. Work over the last years has focused on the role of adaptor protein complex-mediated protein trafficking in neurons using AP-4-associated hereditary spastic paraplegia (AP4B1, AP4M1, AP4S1, AP4E1) as a tractable model. We established that AP-4 cargo proteins, ATG9A and DAGLB, are mislocalized in AP-4 deficient cells, including in neurons derived from patients. Building on this cellular phenotype, we developed a high-throughput assay for small molecule and functional genomics screens. Ongoing work is testing the hypothesis that small molecule modulators of protein trafficking, identified using our high-content imaging platform, can restore key cellular mechanisms in AP-4-associated hereditary spastic paraplegia in vitro and in vivo.

Key Publications (PMCIDs)

AP-4-mediated axonal transport controls endocannabinoid production in neurons
Davies AK, Alecu JE, Ziegler M, Vasilopoulou CG, Merciai F, Jumo H, Afshar Saber W, Sahin M, Ebrahimi-Fakhari *, Borner *.
Nature Communications, in press

High-throughput imaging of ATG9A distribution as a diagnostic functional assay for adaptor protein complex 4-associated hereditary spastic paraplegia.
Ebrahimi-Fakhari D, Alecu JE, Brechmann B, Ziegler M, Eberhardt K, Jumo H, D'Amore A, Habibzadeh P, Faghihi MA, De Bleecker JL, Vuillaumier-Barrot S, Auvin S, Santorelli FM, Neuser S, Popp B, Yang E, Barrett L, Davies AK, Saffari A, Hirst J, Sahin M.
Brain Commun. 2021 Sep 25;3(4):fcab221. doi: 10.1093/braincomms/fcab221. PMID: 34729478; PMCID: PMC8557665

International AP-4-HSP Registry and Natural History Study. Systematic Analysis of Brain MRI Findings in Adaptor Protein Complex 4-Associated Hereditary Spastic Paraplegia.
Ebrahimi-Fakhari D, Alecu JE, Ziegler M, Geisel G, Jordan C, D'Amore A, Yeh RC, Akula SK, Saffari A, Prabhu SP, Sahin M, Yang E
Neurology. 2021 Nov 9;97(19):e1942-e1954. Epub 2021 Sep 20. PMID: 34544818; PMCID: PMC8601212.

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.
Ebrahimi-Fakhari D, Teinert J, Behne R, Wimmer M, D'Amore A, Eberhardt K, Brechmann B, Ziegler M, Jensen DM, Nagabhyrava P, Geisel G, Carmody E, Shamshad U, Dies KA, Yuskaitis CJ, Salussolia CL, Ebrahimi-Fakhari D, Pearson TS, Saffari A, Ziegler A, Kölker S, Volkmann J, Wiesener A, Bearden DR, Lakhani S, Segal D, Udwadia-Hegde A, Martinuzzi A, Hirst J, Perlman S, Takiyama Y, Xiromerisiou G, Vill K, Walker WO, Shukla A, Dubey Gupta R, Dahl N, Aksoy A, Verhelst H, Delgado MR, Kremlikova Pourova R, Sadek AA, Elkhateeb NM, Blumkin L, Brea-Fernández AJ, Dacruz-Álvarez D, Smol T, Ghoumid J, Miguel D, Heine C, Schlump JU, Langen H, Baets J, Bulk S, Darvish H, Bakhtiari S, Kruer MC, Lim-Melia E, Aydinli N, Alanay Y, El-Rashidy O, Nampoothiri S, Patel C, Beetz C, Bauer P, Yoon G, Guillot M, Miller SP, Bourinaris T, Houlden H, Robelin L, Anheim M, Alamri AS, Mahmoud AAH, Inaloo S, Habibzadeh P, Faghihi MA, Jansen AC, Brock S, Roubertie A, Darras BT, Agrawal PB, Santorelli FM, Gleeson J, Zaki MS, Sheikh SI, Bennett JT, Sahin M.
Brain. 2020 Oct 1;143(10):2929-2944. doi: 10.1093/brain/awz307. PMID: 32979048; PMCID: PMC7780481.

Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking.
Behne R, Teinert J, Wimmer M, D'Amore A, Davies AK, Scarrott JM, Eberhardt K, Brechmann B, Chen IP, Buttermore ED, Barrett L, Dwyer S, Chen T, Hirst J, Wiesener A, Segal D, Martinuzzi A, Duarte ST, Bennett JT, Bourinaris T, Houlden H, Roubertie A, Santorelli FM, Robinson M, Azzouz M, Lipton JO, Borner GHH, Sahin M, Ebrahimi-Fakhari D.
Hum Mol Genet. 2020 Jan 15;29(2):320-334. PMID: 31915823; PMCID: PMC7001721.

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