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Morphological remodeling of C. elegans neurons during aging is modified by compromised protein homeostasis.

Vayndorf EM, Scerbak C, Hunter S, Neuswanger JR, Toth M, Parker JA, Neri C, Driscoll M, Taylor BE - NPJ Aging Mech Dis (2016)

Bottom Line: Our results show that the expression of misfolded proteins in neurodegenerative disease such as Huntington's disease modifies the morphological remodeling that is normally associated with neuronal aging.Our results also show that morphological remodeling of healthy neurons during aging can be regulated by the UPS and other proteostasis pathways.Collectively, our data highlight a model in which morphological remodeling during neuronal aging is strongly affected by disrupted proteostasis and expression of disease-associated, misfolded proteins such as human polyQ-Htt species.

View Article: PubMed Central - PubMed

Affiliation: Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK, USA.

ABSTRACT

Understanding cellular outcomes, such as neuronal remodeling, that are common to both healthy and diseased aging brains is essential to the development of successful brain aging strategies. Here, we used Caenorhabdits elegans to investigate how the expression of proteotoxic triggers, such as polyglutamine (polyQ)-expanded huntingtin and silencing of proteostasis regulators, such as the ubiquitin-proteasome system (UPS) and protein clearance components, may impact the morphological remodeling of individual neurons as animals age. We examined the effects of disrupted proteostasis on the integrity of neuronal cytoarchitecture by imaging a transgenic C. elegans strain in which touch receptor neurons express the first 57 amino acids of the human huntingtin (Htt) gene with expanded polyQs (128Q) and by using neuron-targeted RNA interference in adult wild-type neurons to knockdown genes encoding proteins involved in proteostasis. We found that proteostatic challenges conferred by polyQ-expanded Htt and knockdown of specific genes involved in protein homeostasis can lead to morphological changes that are restricted to specific domains of specific neurons. The age-associated branching of PLM neurons is suppressed by N-ter polyQ-expanded Htt expression, whereas ALM neurons with polyQ-expanded Htt accumulate extended outgrowths and other soma abnormalities. Furthermore, knockdown of genes important for ubiquitin-mediated degradation, lysosomal function, and autophagy modulated these age-related morphological changes in otherwise normal neurons. Our results show that the expression of misfolded proteins in neurodegenerative disease such as Huntington's disease modifies the morphological remodeling that is normally associated with neuronal aging. Our results also show that morphological remodeling of healthy neurons during aging can be regulated by the UPS and other proteostasis pathways. Collectively, our data highlight a model in which morphological remodeling during neuronal aging is strongly affected by disrupted proteostasis and expression of disease-associated, misfolded proteins such as human polyQ-Htt species.

No MeSH data available.


Related in: MedlinePlus

Neuronal aberrations in Pmec-4GFP, polyQ19 and polyQ128 neurons across the lifespan. Animals were grown at 25 °C and imaged on the indicated days. Each bar represents mean ± s.e. (a) Branches per PLM cell increased slightly in Pmec-4GFP, but not in polyQ19 or polyQ128 animals (Pmec-4GFP N = 512, P = 0.893; polyQ19 N = 277, P = 0.692; polyQ128 N = 430; P = 0.898; Wald test). (b) Extended outgrowths per ALM cell increased significantly in polyQ128, but not in Pmec-4GFP or polyQ19 animals (Pmec-4GFP N = 557, P = 0.257; polyQ19 N = 489, P = 0.126; polyQ128 N = 482, P = 0.009). (c) There were significantly more outgrowth connectors per ALM cell in polyQ128 animals on day 3 (P<0.00001) compared with polyQ19 and Pmec-4GFP. A numerical decrease in these connectors over time was not statistically significant (P = 0.213) (Pmec-4GFP N = 557; polyQ19 N = 489; polyQ128 N = 482). GFP, green fluorescent protein; PolyQ, polyglutamine.
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Figure 2: Neuronal aberrations in Pmec-4GFP, polyQ19 and polyQ128 neurons across the lifespan. Animals were grown at 25 °C and imaged on the indicated days. Each bar represents mean ± s.e. (a) Branches per PLM cell increased slightly in Pmec-4GFP, but not in polyQ19 or polyQ128 animals (Pmec-4GFP N = 512, P = 0.893; polyQ19 N = 277, P = 0.692; polyQ128 N = 430; P = 0.898; Wald test). (b) Extended outgrowths per ALM cell increased significantly in polyQ128, but not in Pmec-4GFP or polyQ19 animals (Pmec-4GFP N = 557, P = 0.257; polyQ19 N = 489, P = 0.126; polyQ128 N = 482, P = 0.009). (c) There were significantly more outgrowth connectors per ALM cell in polyQ128 animals on day 3 (P<0.00001) compared with polyQ19 and Pmec-4GFP. A numerical decrease in these connectors over time was not statistically significant (P = 0.213) (Pmec-4GFP N = 557; polyQ19 N = 489; polyQ128 N = 482). GFP, green fluorescent protein; PolyQ, polyglutamine.

Mentions: Neurons of animals with expanded, toxic polyQ repeats (polyQ128) accumulated morphological abnormalities with age, a phenomenon also observed in aging touch neurons without expressed toxic proteins (Figure 1). We found that specific abnormality types differed considerably among strains and cell types. Branches increased over time in Pmec-4GFP PLM neurons, consistent with previous findings.7 However, neither polyQ19 nor polyQ128 PLM neurons exhibited significant branching with age (Figure 2a, Supplementary Figure S3a).


Morphological remodeling of C. elegans neurons during aging is modified by compromised protein homeostasis.

Vayndorf EM, Scerbak C, Hunter S, Neuswanger JR, Toth M, Parker JA, Neri C, Driscoll M, Taylor BE - NPJ Aging Mech Dis (2016)

Neuronal aberrations in Pmec-4GFP, polyQ19 and polyQ128 neurons across the lifespan. Animals were grown at 25 °C and imaged on the indicated days. Each bar represents mean ± s.e. (a) Branches per PLM cell increased slightly in Pmec-4GFP, but not in polyQ19 or polyQ128 animals (Pmec-4GFP N = 512, P = 0.893; polyQ19 N = 277, P = 0.692; polyQ128 N = 430; P = 0.898; Wald test). (b) Extended outgrowths per ALM cell increased significantly in polyQ128, but not in Pmec-4GFP or polyQ19 animals (Pmec-4GFP N = 557, P = 0.257; polyQ19 N = 489, P = 0.126; polyQ128 N = 482, P = 0.009). (c) There were significantly more outgrowth connectors per ALM cell in polyQ128 animals on day 3 (P<0.00001) compared with polyQ19 and Pmec-4GFP. A numerical decrease in these connectors over time was not statistically significant (P = 0.213) (Pmec-4GFP N = 557; polyQ19 N = 489; polyQ128 N = 482). GFP, green fluorescent protein; PolyQ, polyglutamine.
© Copyright Policy - permissions-link
Related In: Results  -  Collection

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Figure 2: Neuronal aberrations in Pmec-4GFP, polyQ19 and polyQ128 neurons across the lifespan. Animals were grown at 25 °C and imaged on the indicated days. Each bar represents mean ± s.e. (a) Branches per PLM cell increased slightly in Pmec-4GFP, but not in polyQ19 or polyQ128 animals (Pmec-4GFP N = 512, P = 0.893; polyQ19 N = 277, P = 0.692; polyQ128 N = 430; P = 0.898; Wald test). (b) Extended outgrowths per ALM cell increased significantly in polyQ128, but not in Pmec-4GFP or polyQ19 animals (Pmec-4GFP N = 557, P = 0.257; polyQ19 N = 489, P = 0.126; polyQ128 N = 482, P = 0.009). (c) There were significantly more outgrowth connectors per ALM cell in polyQ128 animals on day 3 (P<0.00001) compared with polyQ19 and Pmec-4GFP. A numerical decrease in these connectors over time was not statistically significant (P = 0.213) (Pmec-4GFP N = 557; polyQ19 N = 489; polyQ128 N = 482). GFP, green fluorescent protein; PolyQ, polyglutamine.
Mentions: Neurons of animals with expanded, toxic polyQ repeats (polyQ128) accumulated morphological abnormalities with age, a phenomenon also observed in aging touch neurons without expressed toxic proteins (Figure 1). We found that specific abnormality types differed considerably among strains and cell types. Branches increased over time in Pmec-4GFP PLM neurons, consistent with previous findings.7 However, neither polyQ19 nor polyQ128 PLM neurons exhibited significant branching with age (Figure 2a, Supplementary Figure S3a).

Bottom Line: Our results show that the expression of misfolded proteins in neurodegenerative disease such as Huntington's disease modifies the morphological remodeling that is normally associated with neuronal aging.Our results also show that morphological remodeling of healthy neurons during aging can be regulated by the UPS and other proteostasis pathways.Collectively, our data highlight a model in which morphological remodeling during neuronal aging is strongly affected by disrupted proteostasis and expression of disease-associated, misfolded proteins such as human polyQ-Htt species.

View Article: PubMed Central - PubMed

Affiliation: Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK, USA.

ABSTRACT

Understanding cellular outcomes, such as neuronal remodeling, that are common to both healthy and diseased aging brains is essential to the development of successful brain aging strategies. Here, we used Caenorhabdits elegans to investigate how the expression of proteotoxic triggers, such as polyglutamine (polyQ)-expanded huntingtin and silencing of proteostasis regulators, such as the ubiquitin-proteasome system (UPS) and protein clearance components, may impact the morphological remodeling of individual neurons as animals age. We examined the effects of disrupted proteostasis on the integrity of neuronal cytoarchitecture by imaging a transgenic C. elegans strain in which touch receptor neurons express the first 57 amino acids of the human huntingtin (Htt) gene with expanded polyQs (128Q) and by using neuron-targeted RNA interference in adult wild-type neurons to knockdown genes encoding proteins involved in proteostasis. We found that proteostatic challenges conferred by polyQ-expanded Htt and knockdown of specific genes involved in protein homeostasis can lead to morphological changes that are restricted to specific domains of specific neurons. The age-associated branching of PLM neurons is suppressed by N-ter polyQ-expanded Htt expression, whereas ALM neurons with polyQ-expanded Htt accumulate extended outgrowths and other soma abnormalities. Furthermore, knockdown of genes important for ubiquitin-mediated degradation, lysosomal function, and autophagy modulated these age-related morphological changes in otherwise normal neurons. Our results show that the expression of misfolded proteins in neurodegenerative disease such as Huntington's disease modifies the morphological remodeling that is normally associated with neuronal aging. Our results also show that morphological remodeling of healthy neurons during aging can be regulated by the UPS and other proteostasis pathways. Collectively, our data highlight a model in which morphological remodeling during neuronal aging is strongly affected by disrupted proteostasis and expression of disease-associated, misfolded proteins such as human polyQ-Htt species.

No MeSH data available.


Related in: MedlinePlus