Ahfeldt Lab

Neurodegenerative Disease Modeling

Research

Tim AhfeldtWhy some cells are more vulnerable to neurodegenerative disease than others is a fundamental question for which tools are limited. The answer to this question has broad implications for our understanding of pathological mechanisms and the development of pharmacological interventions. Human pluripotent stem cells (hPSCs), which can be differentiated into all cell types, provide an unparalleled tool for studying human neurodegenerative diseases in vitro. For example, Parkinson’s Disease (PD) is characterized by the almost complete loss of midbrain dopaminergic neurons in the substantia nigra pars compacta (SNpc), while the closest relatives in the ventral tegmental area (VTA) are relatively spared. As a post-doctoral research fellow and research associate, I have developed isogenic hPSCs models of Parkinson’s Disease (PD). Using CRISPR gene editing techniques, I have introduced fluorescent reporters and highly penetrant PD-causing mutations and analyzed the differentiated cells on a molecular and functional level and through unbiased data driven ‘OMICs’ technologies (Manuscript in review). Our data suggests that our PD model recapitulates disease aspects found in vivo as we observe selective vulnerability in differentiated midbrain dopaminergic neurons in PD lines providing us with an opportunity to address the question of specific cell type vulnerability in a novel and unique way. In my lab we are expanding this approach. In comparative studies we are looking at all PD causing mutations as well as mutations causal or associated with other neurodegenerative diseases, like Alzheimer’s Disease, Dementia with Lewy Bodies and Parkinsonism’s and the phenotypic consequences in distinct cell types. Using our model system, we aim to disentangle genotype from phenotype and cell-type and identify disease relevant common and unique pathways that hold promise for future therapies.

Contact Us

Ahfeldt Laboratory

Tim Ahfeldt
Principal Investigator
Email

Tatiana Kareva
Associate Researcher/Lab Manager
Email

Publications

1. Ordureau A, Paulo JA, Zhang W, Ahfeldt T, Zhang J, Cohn EF, Hou Z, Heo JM, Rubin
LL, Sidhu SS, Gygi SP, Harper JW. Dynamics of PARKIN-Dependent Mitochondrial
Ubiquitylation in Induced Neurons and Model Systems Revealed by Digital Snapshot
Proteomics. Mol Cell. 2018 Apr 19;70(2):211-227.e8. doi:
10.1016/j.molcel.2018.03.012. Epub 2018 Apr 12. PubMed [citation] PMID: 29656925,
PMCID: PMC5910199

2. Ahfeldt T, Litterman NK, Rubin LL. Studying human disease using human neurons.
Brain Res. 2017 Feb 1;1656:40-48. doi: 10.1016/j.brainres.2016.03.051. Epub 2016
Apr 6. Review. PubMed [citation] PMID: 27060768, PMCID: PMC5053850

3. Madison JM, Zhou F, Nigam A, Hussain A, Barker DD, Nehme R, van der Ven K, Hsu J,
Wolf P, Fleishman M, O’Dushlaine C, Rose S, Chambert K, Lau FH, Ahfeldt T,
Rueckert EH, Sheridan SD, Fass DM, Nemesh J, Mullen TE, Daheron L, McCarroll S,
et al. Characterization of bipolar disorder patient-specific induced pluripotent
stem cells from a family reveals neurodevelopmental and mRNA expression
abnormalities. Mol Psychiatry. 2015 Jun;20(6):703-17. doi: 10.1038/mp.2015.7.
Epub 2015 Mar 3. PubMed [citation] PMID: 25733313, PMCID: PMC4440839

4. Ding Q, Lee YK, Schaefer EA, Peters DT, Veres A, Kim K, Kuperwasser N, Motola DL,
Meissner TB, Hendriks WT, Trevisan M, Gupta RM, Moisan A, Banks E, Friesen M,
Schinzel RT, Xia F, Tang A, Xia Y, Figueroa E, Wann A, Ahfeldt T, et al. A TALEN
genome-editing system for generating human stem cell-based disease models. Cell
Stem Cell. 2013 Feb 7;12(2):238-51. doi: 10.1016/j.stem.2012.11.011. Epub 2012
Dec 13. PubMed [citation] PMID: 23246482, PMCID: PMC3570604

5. Mou H, Zhao R, Sherwood R, Ahfeldt T, Lapey A, Wain J, Sicilian L, Izvolsky K,
Musunuru K, Cowan C, Rajagopal J. Generation of multipotent lung and airway
progenitors from mouse ESCs and patient-specific cystic fibrosis iPSCs. Cell Stem
Cell. 2012 Apr 6;10(4):385-97. doi: 10.1016/j.stem.2012.01.018. Erratum in: Cell
Stem Cell. 2012 May 4;10(5):635. PubMed [citation] PMID: 22482504, PMCID:
PMC3474327

6. Ahfeldt T, Schinzel RT, Lee YK, Hendrickson D, Kaplan A, Lum DH, Camahort R, Xia
F, Shay J, Rhee EP, Clish CB, Deo RC, Shen T, Lau FH, Cowley A, Mowrer G,
Al-Siddiqi H, Nahrendorf M, Musunuru K, Gerszten RE, Rinn JL, Cowan CA.
Programming human pluripotent stem cells into white and brown adipocytes. Nat
Cell Biol. 2012 Jan 15;14(2):209-19. doi: 10.1038/ncb2411. PubMed [citation] PMID: 22246346, PMCID: PMC3385947

7. Lau FH, Deo RC, Mowrer G, Caplin J, Ahfeldt T, Kaplan A, Ptaszek L, Walker JD,
Rosengard BR, Cowan CA. Pattern specification and immune response transcriptional
signatures of pericardial and subcutaneous adipose tissue. PLoS One.
2011;6(10):e26092. doi: 10.1371/journal.pone.0026092. Epub 2011 Oct 11. PubMed[citation] PMID: 22022522, PMCID: PMC3191160

8. Schinzel RT, Ahfeldt T, Lau FH, Lee YK, Cowley A, Shen T, Peters D, Lum DH, Cowan
CA. Efficient culturing and genetic manipulation of human pluripotent stem cells.
PLoS One. 2011;6(12):e27495. doi: 10.1371/journal.pone.0027495. Epub 2011 Dec 15.
PubMed [citation] PMID: 22194785, PMCID: PMC3240614

9. Warren L, Manos PD, Ahfeldt T, Loh YH, Li H, Lau F, Ebina W, Mandal PK, Smith ZD,
Meissner A, Daley GQ, Brack AS, Collins JJ, Cowan C, Schlaeger TM, Rossi DJ.
Highly efficient reprogramming to pluripotency and directed differentiation of
human cells with synthetic modified mRNA. Cell Stem Cell. 2010 Nov 5;7(5):618-30.
doi: 10.1016/j.stem.2010.08.012. Epub 2010 Sep 30. PubMed [citation] PMID:
20888316, PMCID: PMC3656821

10. Musunuru K, Strong A, Frank-Kamenetsky M, Lee NE, Ahfeldt T, Sachs KV, Li X, Li
H, Kuperwasser N, Ruda VM, Pirruccello JP, Muchmore B, Prokunina-Olsson L, Hall
JL, Schadt EE, Morales CR, Lund-Katz S, Phillips MC, Wong J, Cantley W, Racie T,
Ejebe KG, et al. From noncoding variant to phenotype via SORT1 at the 1p13
cholesterol locus. Nature. 2010 Aug 5;466(7307):714-9. doi: 10.1038/nature09266.
PubMed [citation] PMID: 20686566, PMCID: PMC3062476

11. Lau F, Ahfeldt T, Osafune K, Akustsu H, Cowan CA. Induced pluripotent stem (iPS)
cells: an up-to-the-minute review. F1000 Biol Rep. 2009 Nov 16;1:84. doi:
10.3410/B1-84. PubMed [citation] PMID: 20948605, PMCID: PMC2948253

12. Eminli S, Foudi A, Stadtfeld M, Maherali N, Ahfeldt T, Mostoslavsky G, Hock H,
Hochedlinger K. Differentiation stage determines potential of hematopoietic cells
for reprogramming into induced pluripotent stem cells. Nat Genet. 2009
Sep;41(9):968-76. doi: 10.1038/ng.428. Epub 2009 Aug 9. PubMed [citation] PMID:
19668214, PMCID: PMC3987895

13. Maherali N, Ahfeldt T, Rigamonti A, Utikal J, Cowan C, Hochedlinger K. A
high-efficiency system for the generation and study of human induced pluripotent
stem cells. Cell Stem Cell. 2008 Sep 11;3(3):340-5. doi:
10.1016/j.stem.2008.08.003. PubMed [citation] PMID: 18786420, PMCID: PMC3987901

14. Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C,
Hochedlinger K, Daley GQ. Disease-specific induced pluripotent stem cells. Cell.
2008 Sep 5;134(5):877-86. doi: 10.1016/j.cell.2008.07.041. Epub 2008 Aug 7.
PubMed [citation] PMID: 18691744, PMCID: PMC2633781

15. Composition and methods for enhanced knock-in reporter gene expression
Ahfeldt T, Rubin LL.
USA 62/443,543,.
My Bibliography [patent]

16. Differentiation into brown adipocytes
Ahfeldt T, Cowan C, Lee Y, Schinzel R.
USA WO2013082106 A1.
My Bibliography [patent]

17. Compositions and methods of generating reprogrammed adipocyte cells and methods
of use therefore
Ahfeldt T, Lum DH, Cowan C.
USA US20120219530 A1.
My Bibliography [patent]

18. Compositions comprising hepatocyte-like cells and uses thereof
Ahfeldt T, Cowan C, Lum DH, Pryor HI, Vacanti JP.
USA WO2010014949 A3.
My Bibliography [patent]

Meet the Team

noimageprofileTim Ahfeldt
Principal Investigator

noimageprofileTatiana Kareva
Associate Researcher / Lab Manager

noimageprofileLeili Sarrafha
Graduate Student