Dictyostelium discoideum as a Model for Investigating Neurodegenerative Diseases

Abstract

The social amoeba Dictyostelium discoideum is a model organism that is used to investigate many cellular processes including chemotaxis, cell motility, cell differentiation, and human disease pathogenesis. While many single-cellular model systems lack homologs of human disease genes, Dictyostelium’s genome encodes for many genes that are implicated in human diseases including neurodegenerative diseases. Due to its short doubling time along with the powerful genetic tools that enable rapid genetic screening, and the ease of creating knockout cell lines, Dictyostelium is an attractive model organism for both interrogating the normal function of genes implicated in neurodegeneration and for determining pathogenic mechanisms that cause disease. Here we review the literature involving the use of Dictyostelium to interrogate genes implicated in neurodegeneration and highlight key questions that can be addressed using Dictyostelium as a model organism.

Naegleria genus pangenome reveals new structural and functional insights into the versatility of these free-living amoebae

“…Interestingly, we also noticed that Naegleria genes share similarities with human genes ( Supplementary Table S4 ). Human orthologues have previously been found in the social amoeba Dictyostelium discoideum ( Eichinger et al, 2005 ); and due to the strong protein homology, this amoeba is currently being used as a model to study genes related to human degenerative diseases ( Haver and Scaglione, 2021 ). To assess if Naegleria could be used to investigate the functions of genes related to human disease, we performed a filtering of significant matches from Blast similarity searches between Naegleria and Homo sapiens protein sequences, using a stringent threshold E-value < 10E-20 and protein similarity extending over 65% ( Table 2 ) with sequence coverage above 80%.…”

“…Because of a high number of conserved features comparable to Animalia (including human), these versatile protists could be used as a non-mammalian model to study of eukaryotic cell biology features such as resistance to temperature, cell-autonomous defense mechanisms, and host-pathogen interaction. At the moment, the non-mammalian host models predominantly used belong to the genera Acanthamoeba and Dictyostelium (phylum Amoebozoa; Eichinger et al, 2005 ; Chen et al, 2007 ; Sandström et al, 2011 ; Dunn et al, 2018 ; Swart et al, 2018 ; Haver and Scaglione, 2021 ). Although they have proven to be particularly useful to study different eukaryotic mechanisms such as host-pathogen interaction, cell motility, chemotaxis, phagocytosis, and more recently autophagy and microbiome formation, one of the major drawbacks in using these amoebae is that most of them do not grow at “elevated” temperatures such as the human body temperature.…”

Insights on Microsatellite Characteristics, Evolution, and Function From the Social Amoeba Dictyostelium discoideum

“…There are several human diseases associated with microsatellite expansion ( Ranum and Day, 2002 ; Orr and Zoghbi, 2007 ; Brouwer et al, 2009 ). However, despite the many orthologs of human disease-associated genes and the seeming lack of harmful effects from its highly repetitive genome, relatively little research has been done in Dictyostelium on diseases caused by microsatellite expansion ( Myre et al, 2011 ; Wang et al, 2011 ; Myre, 2012 ; Olmos et al, 2020 ; Haver and Scaglione, 2021 ). One microsatellite-associated disease that has been modeled in Dictyostelium is Huntington’s Disease.…”

“…Furthermore, due to its repeat-rich genome Dictyostelium is an interesting organism to investigate cellular phenomena associated with expanded microsatellites in a tractable and easy-to-use organism ( Figure 1 ; Bozzaro, 2013 ; Pears and Lakin, 2014 ; Malinovska and Alberti, 2015 ; Haver and Scaglione, 2021 ; Pears and Gross, 2021 ; Pears et al, 2021 ). Here we can begin to address many questions of relevance to human health.…”

Mechanistic Insight into the Suppression of Polyglutamine Aggregation by SRCP1

“…Polyglutamine aggregation has been investigated in a wide variety of model organisms. In most models, expression of polyglutamine-expanded proteins results in the formation of aggregates. − One model organism, Dictyostelium discoideum , is unique in that it naturally encodes long polyglutamine tracts and is resistant to polyglutamine aggregation. − Utilizing Dictyostelium as a model system for polyglutamine aggregation is one way to gain insight into how nature has dealt with this problem.…”