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Use of Caenorhabditis elegans as a model to study Alzheimer's disease and other neurodegenerative diseases.

Alexander AG, Marfil V, Li C - Front Genet (2014)

Bottom Line: It is a progressive neurodegenerative disorder, characterized by the prevalence of extracellular Aβ plaques and intracellular neurofibrillary tangles, derived from the proteolysis of the amyloid precursor protein (APP) and the hyperphosphorylation of microtubule-associated protein tau, respectively.This article addresses the insights C. elegans provide in studying AD and other neurodegenerative diseases.Additionally, we explore the advantages and drawbacks associated with using this model.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, City College of New York New York, NY, USA ; Department of Biology, The Graduate Center, City University of New York New York, NY, USA.

ABSTRACT
Advances in research and technology has increased our quality of life, allowed us to combat diseases, and achieve increased longevity. Unfortunately, increased longevity is accompanied by a rise in the incidences of age-related diseases such as Alzheimer's disease (AD). AD is the sixth leading cause of death, and one of the leading causes of dementia amongst the aged population in the USA. It is a progressive neurodegenerative disorder, characterized by the prevalence of extracellular Aβ plaques and intracellular neurofibrillary tangles, derived from the proteolysis of the amyloid precursor protein (APP) and the hyperphosphorylation of microtubule-associated protein tau, respectively. Despite years of extensive research, the molecular mechanisms that underlie the pathology of AD remain unclear. Model organisms, such as the nematode, Caenorhabditis elegans, present a complementary approach to addressing these questions. C. elegans has many advantages as a model system to study AD and other neurodegenerative diseases. Like their mammalian counterparts, they have complex biochemical pathways, most of which are conserved. Genes in which mutations are correlated with AD have counterparts in C. elegans, including an APP-related gene, apl-1, a tau homolog, ptl-1, and presenilin homologs, such as sel-12 and hop-1. Since the neuronal connectivity in C. elegans has already been established, C. elegans is also advantageous in modeling learning and memory impairments seen during AD. This article addresses the insights C. elegans provide in studying AD and other neurodegenerative diseases. Additionally, we explore the advantages and drawbacks associated with using this model.

No MeSH data available.


Related in: MedlinePlus

Similarities and differences between human tau and Caenorhabditis elegans PTL-1. (A) Schematic representation of human microtubule binding proteins (MAPs) family, including tau isoforms and C. elegans PTL-1 isoforms. (B) Comparison between tau functions in humans (top) and C. elegans PTL-1/tau functions (bottom). Top. Tau has a physiological role in promoting and maintaining microtubule stability. In pathological conditions tau is hyperphosphorylated and self-aggregates into paired helical filaments (PHFs) that can form intracellular neurofibrillary tangles (NFT). Bottom. C. elegans PTL-1/tau binds microtubules and induces microtubule assembly. It also affects synaptic transport through motor proteins UNC-104/KIF1a/kinesin-3, UNC-116/kinesin-1, and DLC-1/dynein. PTL-1/tau is also important for C. elegans mechanosensation and aging.
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Figure 3: Similarities and differences between human tau and Caenorhabditis elegans PTL-1. (A) Schematic representation of human microtubule binding proteins (MAPs) family, including tau isoforms and C. elegans PTL-1 isoforms. (B) Comparison between tau functions in humans (top) and C. elegans PTL-1/tau functions (bottom). Top. Tau has a physiological role in promoting and maintaining microtubule stability. In pathological conditions tau is hyperphosphorylated and self-aggregates into paired helical filaments (PHFs) that can form intracellular neurofibrillary tangles (NFT). Bottom. C. elegans PTL-1/tau binds microtubules and induces microtubule assembly. It also affects synaptic transport through motor proteins UNC-104/KIF1a/kinesin-3, UNC-116/kinesin-1, and DLC-1/dynein. PTL-1/tau is also important for C. elegans mechanosensation and aging.

Mentions: Accumulation of neurofibrillary tangles in cell bodies is another hallmark characteristic of AD and other neurodegenerative disorders. The major component of these tangles is tau, which belongs to the family of microtubule-associated proteins (MAPs) that includes MAP2 and MAP4 (Lee et al., 1988; Lewis et al., 1988; Goedert et al., 1989b; Chapin and Bulinski, 1991). MAPs share characteristic homology domains, including a proline-rich domain and a region of a variable number of tandem amino acid repeats (Figure 3A; Goedert et al., 1988, 1989a,b, 1992a; Lee et al., 1988; Lewis et al., 1988; Aizawa et al., 1990). Tau is the predominant MAP expressed in axons, while MAP2 is expressed in dendrites (Matus et al., 1981; Binder et al., 1985) and MAP4 is expressed in dividing cells (Bulinski and Borisy, 1980). MAPs bind microtubules and are responsible for promoting microtubule assembly and stability (reviewed in Amos and Schlieper, 2005). MAP family members appear to have redundant functions; mice in which tau was knocked out were viable, but showed increased levels of MAP1A (Harada et al., 1994), suggesting that upregulation of MAP1A can compensate for the lack of tau in vivo. Tau phosphorylation affects its ability to bind microtubules and can cause a conformational change that favors tubulin assembly (Figure 3B; Feijoo et al., 2005). Aberrant hyperphosphorylation of tau, however, impairs its ability to bind microtubules, thus resulting in their disassembly (Lindwall and Cole, 1984; Biernat et al., 1993; Bramblett et al., 1993). In addition, phosphorylated tau self-aggregates into PHFs and presumably generates the intracellular neurofibrillary tangles characteristic of AD patients (Figure 3B; Goedert et al., 1992b; Alonso et al., 1996, 1997, 2001; Billingsley and Kincaid, 1997).


Use of Caenorhabditis elegans as a model to study Alzheimer's disease and other neurodegenerative diseases.

Alexander AG, Marfil V, Li C - Front Genet (2014)

Similarities and differences between human tau and Caenorhabditis elegans PTL-1. (A) Schematic representation of human microtubule binding proteins (MAPs) family, including tau isoforms and C. elegans PTL-1 isoforms. (B) Comparison between tau functions in humans (top) and C. elegans PTL-1/tau functions (bottom). Top. Tau has a physiological role in promoting and maintaining microtubule stability. In pathological conditions tau is hyperphosphorylated and self-aggregates into paired helical filaments (PHFs) that can form intracellular neurofibrillary tangles (NFT). Bottom. C. elegans PTL-1/tau binds microtubules and induces microtubule assembly. It also affects synaptic transport through motor proteins UNC-104/KIF1a/kinesin-3, UNC-116/kinesin-1, and DLC-1/dynein. PTL-1/tau is also important for C. elegans mechanosensation and aging.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 3: Similarities and differences between human tau and Caenorhabditis elegans PTL-1. (A) Schematic representation of human microtubule binding proteins (MAPs) family, including tau isoforms and C. elegans PTL-1 isoforms. (B) Comparison between tau functions in humans (top) and C. elegans PTL-1/tau functions (bottom). Top. Tau has a physiological role in promoting and maintaining microtubule stability. In pathological conditions tau is hyperphosphorylated and self-aggregates into paired helical filaments (PHFs) that can form intracellular neurofibrillary tangles (NFT). Bottom. C. elegans PTL-1/tau binds microtubules and induces microtubule assembly. It also affects synaptic transport through motor proteins UNC-104/KIF1a/kinesin-3, UNC-116/kinesin-1, and DLC-1/dynein. PTL-1/tau is also important for C. elegans mechanosensation and aging.
Mentions: Accumulation of neurofibrillary tangles in cell bodies is another hallmark characteristic of AD and other neurodegenerative disorders. The major component of these tangles is tau, which belongs to the family of microtubule-associated proteins (MAPs) that includes MAP2 and MAP4 (Lee et al., 1988; Lewis et al., 1988; Goedert et al., 1989b; Chapin and Bulinski, 1991). MAPs share characteristic homology domains, including a proline-rich domain and a region of a variable number of tandem amino acid repeats (Figure 3A; Goedert et al., 1988, 1989a,b, 1992a; Lee et al., 1988; Lewis et al., 1988; Aizawa et al., 1990). Tau is the predominant MAP expressed in axons, while MAP2 is expressed in dendrites (Matus et al., 1981; Binder et al., 1985) and MAP4 is expressed in dividing cells (Bulinski and Borisy, 1980). MAPs bind microtubules and are responsible for promoting microtubule assembly and stability (reviewed in Amos and Schlieper, 2005). MAP family members appear to have redundant functions; mice in which tau was knocked out were viable, but showed increased levels of MAP1A (Harada et al., 1994), suggesting that upregulation of MAP1A can compensate for the lack of tau in vivo. Tau phosphorylation affects its ability to bind microtubules and can cause a conformational change that favors tubulin assembly (Figure 3B; Feijoo et al., 2005). Aberrant hyperphosphorylation of tau, however, impairs its ability to bind microtubules, thus resulting in their disassembly (Lindwall and Cole, 1984; Biernat et al., 1993; Bramblett et al., 1993). In addition, phosphorylated tau self-aggregates into PHFs and presumably generates the intracellular neurofibrillary tangles characteristic of AD patients (Figure 3B; Goedert et al., 1992b; Alonso et al., 1996, 1997, 2001; Billingsley and Kincaid, 1997).

Bottom Line: It is a progressive neurodegenerative disorder, characterized by the prevalence of extracellular Aβ plaques and intracellular neurofibrillary tangles, derived from the proteolysis of the amyloid precursor protein (APP) and the hyperphosphorylation of microtubule-associated protein tau, respectively.This article addresses the insights C. elegans provide in studying AD and other neurodegenerative diseases.Additionally, we explore the advantages and drawbacks associated with using this model.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, City College of New York New York, NY, USA ; Department of Biology, The Graduate Center, City University of New York New York, NY, USA.

ABSTRACT
Advances in research and technology has increased our quality of life, allowed us to combat diseases, and achieve increased longevity. Unfortunately, increased longevity is accompanied by a rise in the incidences of age-related diseases such as Alzheimer's disease (AD). AD is the sixth leading cause of death, and one of the leading causes of dementia amongst the aged population in the USA. It is a progressive neurodegenerative disorder, characterized by the prevalence of extracellular Aβ plaques and intracellular neurofibrillary tangles, derived from the proteolysis of the amyloid precursor protein (APP) and the hyperphosphorylation of microtubule-associated protein tau, respectively. Despite years of extensive research, the molecular mechanisms that underlie the pathology of AD remain unclear. Model organisms, such as the nematode, Caenorhabditis elegans, present a complementary approach to addressing these questions. C. elegans has many advantages as a model system to study AD and other neurodegenerative diseases. Like their mammalian counterparts, they have complex biochemical pathways, most of which are conserved. Genes in which mutations are correlated with AD have counterparts in C. elegans, including an APP-related gene, apl-1, a tau homolog, ptl-1, and presenilin homologs, such as sel-12 and hop-1. Since the neuronal connectivity in C. elegans has already been established, C. elegans is also advantageous in modeling learning and memory impairments seen during AD. This article addresses the insights C. elegans provide in studying AD and other neurodegenerative diseases. Additionally, we explore the advantages and drawbacks associated with using this model.

No MeSH data available.


Related in: MedlinePlus