Limits...
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

Gentle touch response across the lifespan in Pmec-4GFP, polyQ19 and polyQ128 animals. Animals were grown at 25 °C and tested for gentle-touch response on the indicated days. Anterior (a) and posterior (b) gentle-touch response during adulthood in Pmec-4GFP, polyQ19 and poly128 animals measured on a scale of number of responses to 5 tests of gently provoking animals on the tail or head with an eyelash. The analysis was run on three independent trials and a compilation of observations per time point is presented to obtain each N. Each bar represents mean ± s.e. There was a statistically significant decrease in both anterior and posterior touch response in every strain (N = P<0.0001, Wald test). No differences in slope were detected among strains with the exception of anterior touch response polyQ19 versus polyQ0 (P = 0.02). Anterior: polyQ0 N = 65 (d3), 68 (d5), 56 (d7), 47 (d9), 33 (day11); polyQ19 N = 51 (d3), 56 (d5), 51 (d7), 64 (d9), 33(d11); polyQ128 N = 68 (d3), 61 (d5), 57 (d7), 68 (d9), 21 (d11). Posterior: polyQ0 N = 73 (d3), 71 (d5), 56 (d7), 47 (d9), 33 d11); polyQ19 N = 51 (d3), 56 (d5), 51 (d7), 64 (d9), 20 (d11); polyQ128 N = 68 (d3), 61 (d5), 57 (d7), 68 (d9), 21 (d11). (c) Spearman correlation plot: extended outgrowths in polyQ128 animals versus mobility. Youthful animals move spontaneously (Class A) and progressively decline as they age, requiring gentle prodding to move (Class B), or barely move at all even after prodding (Class C).20 (N = 226, ρ = − 0.349, P<0.001). d, day; GFP, green fluorescent protein; PolyQ, polyglutamine.
© Copyright Policy - permissions-link
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4920063&req=5

Figure 3: Gentle touch response across the lifespan in Pmec-4GFP, polyQ19 and polyQ128 animals. Animals were grown at 25 °C and tested for gentle-touch response on the indicated days. Anterior (a) and posterior (b) gentle-touch response during adulthood in Pmec-4GFP, polyQ19 and poly128 animals measured on a scale of number of responses to 5 tests of gently provoking animals on the tail or head with an eyelash. The analysis was run on three independent trials and a compilation of observations per time point is presented to obtain each N. Each bar represents mean ± s.e. There was a statistically significant decrease in both anterior and posterior touch response in every strain (N = P<0.0001, Wald test). No differences in slope were detected among strains with the exception of anterior touch response polyQ19 versus polyQ0 (P = 0.02). Anterior: polyQ0 N = 65 (d3), 68 (d5), 56 (d7), 47 (d9), 33 (day11); polyQ19 N = 51 (d3), 56 (d5), 51 (d7), 64 (d9), 33(d11); polyQ128 N = 68 (d3), 61 (d5), 57 (d7), 68 (d9), 21 (d11). Posterior: polyQ0 N = 73 (d3), 71 (d5), 56 (d7), 47 (d9), 33 d11); polyQ19 N = 51 (d3), 56 (d5), 51 (d7), 64 (d9), 20 (d11); polyQ128 N = 68 (d3), 61 (d5), 57 (d7), 68 (d9), 21 (d11). (c) Spearman correlation plot: extended outgrowths in polyQ128 animals versus mobility. Youthful animals move spontaneously (Class A) and progressively decline as they age, requiring gentle prodding to move (Class B), or barely move at all even after prodding (Class C).20 (N = 226, ρ = − 0.349, P<0.001). d, day; GFP, green fluorescent protein; PolyQ, polyglutamine.

Mentions: Whether specific morphological changes in aging touch neurons are associated with neuronal impairment is not clear.7–9 To address whether form reflects function in the polyQ model, we first established a pattern of functional decline in our model strains (Figures 3a,b). Next, we probed for correlations between morphological abnormalities and function, with cell-type-specific analysis. For naturally aging PLM neurons in the Pmec-4GFP line, branches did not correlate with compromised posterior touch response over adult life (ρ = 0.07, P = 0.28). The lack of branches in PLM neurons of polyQ19 or polyQ128 animals precluded correlation analyses for these strains. Thus, branches did not predict posterior touch dysfunction for aging wild-type touch neurons, consistent with recent suggestions that branches might actually be preferentially produced in successfully aging PLM neurons.19


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)

Gentle touch response across the lifespan in Pmec-4GFP, polyQ19 and polyQ128 animals. Animals were grown at 25 °C and tested for gentle-touch response on the indicated days. Anterior (a) and posterior (b) gentle-touch response during adulthood in Pmec-4GFP, polyQ19 and poly128 animals measured on a scale of number of responses to 5 tests of gently provoking animals on the tail or head with an eyelash. The analysis was run on three independent trials and a compilation of observations per time point is presented to obtain each N. Each bar represents mean ± s.e. There was a statistically significant decrease in both anterior and posterior touch response in every strain (N = P<0.0001, Wald test). No differences in slope were detected among strains with the exception of anterior touch response polyQ19 versus polyQ0 (P = 0.02). Anterior: polyQ0 N = 65 (d3), 68 (d5), 56 (d7), 47 (d9), 33 (day11); polyQ19 N = 51 (d3), 56 (d5), 51 (d7), 64 (d9), 33(d11); polyQ128 N = 68 (d3), 61 (d5), 57 (d7), 68 (d9), 21 (d11). Posterior: polyQ0 N = 73 (d3), 71 (d5), 56 (d7), 47 (d9), 33 d11); polyQ19 N = 51 (d3), 56 (d5), 51 (d7), 64 (d9), 20 (d11); polyQ128 N = 68 (d3), 61 (d5), 57 (d7), 68 (d9), 21 (d11). (c) Spearman correlation plot: extended outgrowths in polyQ128 animals versus mobility. Youthful animals move spontaneously (Class A) and progressively decline as they age, requiring gentle prodding to move (Class B), or barely move at all even after prodding (Class C).20 (N = 226, ρ = − 0.349, P<0.001). d, day; GFP, green fluorescent protein; PolyQ, polyglutamine.
© Copyright Policy - permissions-link
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4920063&req=5

Figure 3: Gentle touch response across the lifespan in Pmec-4GFP, polyQ19 and polyQ128 animals. Animals were grown at 25 °C and tested for gentle-touch response on the indicated days. Anterior (a) and posterior (b) gentle-touch response during adulthood in Pmec-4GFP, polyQ19 and poly128 animals measured on a scale of number of responses to 5 tests of gently provoking animals on the tail or head with an eyelash. The analysis was run on three independent trials and a compilation of observations per time point is presented to obtain each N. Each bar represents mean ± s.e. There was a statistically significant decrease in both anterior and posterior touch response in every strain (N = P<0.0001, Wald test). No differences in slope were detected among strains with the exception of anterior touch response polyQ19 versus polyQ0 (P = 0.02). Anterior: polyQ0 N = 65 (d3), 68 (d5), 56 (d7), 47 (d9), 33 (day11); polyQ19 N = 51 (d3), 56 (d5), 51 (d7), 64 (d9), 33(d11); polyQ128 N = 68 (d3), 61 (d5), 57 (d7), 68 (d9), 21 (d11). Posterior: polyQ0 N = 73 (d3), 71 (d5), 56 (d7), 47 (d9), 33 d11); polyQ19 N = 51 (d3), 56 (d5), 51 (d7), 64 (d9), 20 (d11); polyQ128 N = 68 (d3), 61 (d5), 57 (d7), 68 (d9), 21 (d11). (c) Spearman correlation plot: extended outgrowths in polyQ128 animals versus mobility. Youthful animals move spontaneously (Class A) and progressively decline as they age, requiring gentle prodding to move (Class B), or barely move at all even after prodding (Class C).20 (N = 226, ρ = − 0.349, P<0.001). d, day; GFP, green fluorescent protein; PolyQ, polyglutamine.
Mentions: Whether specific morphological changes in aging touch neurons are associated with neuronal impairment is not clear.7–9 To address whether form reflects function in the polyQ model, we first established a pattern of functional decline in our model strains (Figures 3a,b). Next, we probed for correlations between morphological abnormalities and function, with cell-type-specific analysis. For naturally aging PLM neurons in the Pmec-4GFP line, branches did not correlate with compromised posterior touch response over adult life (ρ = 0.07, P = 0.28). The lack of branches in PLM neurons of polyQ19 or polyQ128 animals precluded correlation analyses for these strains. Thus, branches did not predict posterior touch dysfunction for aging wild-type touch neurons, consistent with recent suggestions that branches might actually be preferentially produced in successfully aging PLM neurons.19

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