Christopher D. Link

  The long-term goal of my research is to understand the cellular and molecular basis of age-associated neurodegenerative diseases, particularly Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS).  Towards this goal, I was the first researcher to develop a transgenic invertebrate model for a human neurodegenerative disease, by engineering the intensely studied model nematode C. elegans to express human b-amyloid peptide (Link, 1995).  My lab's work in C. elegans demonstrated that TDP-43, a central player in ALS/FTD pathology, limits the accumulation of double-stranded RNA (dsRNA) (Saldi et al, 2014).  As mammalian models have improved, and genetic studies have implicated vertebrate-specific functions (e.g., microglia and neuroinflammation) in neurodegenerative diseases, my lab has shifted its focus to mammalian cell culture and transcriptome analyses.   In this regard, my lab has characterized transcriptome changes induced by trisomy 21 (i.e., APP triplication) in iPSCs and differentiated neurons (Gonzales et al, 2018) and knockdown of TDP-43 in primary astrocytes (LaRocca et al, 2019). Our work in C. elegans has also led us to focus on the expression of repetitive element sequences, leading to novel analyses of ALS brain transcriptome data (Prudencio et al, 2017) and a mouse C9orf72 model (Zhang et al, 2019).  Current studies are focused on the functions of the tau protein using tau knockout iPSCs and determining the distribution, origin, and pathological relevance of dsRNA in Alzheimer's and other neurodegenerative diseases.  Both of these current studies involve multielectrode array analyses employing a human astrocyte/neuron culture system that we have recently developed (Lemieux et al 2024).

Selected Publications:

Link, C.D. (1995). Expression of human b amyloid peptide in transgenic Caenorhabditis elegans. Proceedings of the National Academy of Sciences USA, 92, 9368-9372. PMCID: PMC40986

Saldi TK, Ash PEA, Wilson G, Gonzales P, Garrido-Lecca A, Roberts CM, Dostal V, Gendron TF, Stein LD, Blumenthal T, Petrucelli L, Link CD.  (2014) TDP-1, the C. elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA.  EMBO J  Dec 17;33(24):2947-66. PMCID: PMC4282642

Gonzales PK, Roberts CM, Fonte V, Jacobsen C, Stein GH, Link CD. (2018) Transcriptome analysis of genetically matched human induced pluripotent stem cells disomic or trisomic for chromosome 21.  PLoS One. Mar 27;13(3):e0194581. doi: 10.1371 PMID:29584757

Lemieux MR, Freigassner B, Hanson JL, Thathey Z, Opp MR, Hoeffer CA, Link CD. Multielectrode array characterization of human induced pluripotent stem cell derived neurons in co-culture with primary human astrocytes.  PLoS One 2024 Jun 25;19(6):e0303901. doi: 10.1371/journal.pone.0303901. eCollection 2024.