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Explaining intermediate filament accumulation in giant axonal neuropathy.

Opal P, Goldman RD - Rare Dis (2013)

Bottom Line: Although a range of cell types are affected in GAN, neurons display the most severe pathology, with neuronal intermediate filament accumulation and aggregation; this in turn causes axonal swellings or "giant axons." A mechanistic understanding of GAN IF pathology has eluded researchers for many years.In a recent study(1) we demonstrate that the normal function of gigaxonin is to regulate the degradation of IF proteins via the proteasome.Our findings present the first direct link between GAN mutations and IF pathology; moreover, given the importance of IF aggregations in a wide range of disease conditions, our findings could have wider ramifications.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Molecular Biology; Northwestern University Feinberg School of Medicine; Chicago, IL USA ; Davee Department of Neurology; Northwestern University Feinberg School of Medicine; Chicago, IL USA.

ABSTRACT
Giant axonal neuropathy (GAN)(1) is a rare autosomal recessive neurological disorder caused by mutations in the GAN gene that encodes gigaxonin, a member of the BTB/Kelch family of E3 ligase adaptor proteins.(1) This disease is characterized by the aggregation of Intermediate Filaments (IF)-cytoskeletal elements that play important roles in cell physiology including the regulation of cell shape, motility, mechanics and intra-cellular signaling. Although a range of cell types are affected in GAN, neurons display the most severe pathology, with neuronal intermediate filament accumulation and aggregation; this in turn causes axonal swellings or "giant axons." A mechanistic understanding of GAN IF pathology has eluded researchers for many years. In a recent study(1) we demonstrate that the normal function of gigaxonin is to regulate the degradation of IF proteins via the proteasome. Our findings present the first direct link between GAN mutations and IF pathology; moreover, given the importance of IF aggregations in a wide range of disease conditions, our findings could have wider ramifications.

No MeSH data available.


Related in: MedlinePlus

Figure 2. Gigaxonin overexpression clears IF in fibroblasts (A) and neurons (B). In neurons this is likely to lead to improvement of axonal transport of organelles such as mitochondria as they are no longer hindered by IF aggregation.
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Figure 2: Figure 2. Gigaxonin overexpression clears IF in fibroblasts (A) and neurons (B). In neurons this is likely to lead to improvement of axonal transport of organelles such as mitochondria as they are no longer hindered by IF aggregation.

Mentions: Despite numerous unanswered questions, we believe that our results convincingly demonstrate that gigaxonin is an important player in the degradation of IF. Clearly, this is an important insight for GAN. We speculate that gigaxonin might play a much broader role in a number of diseases where IF accumulate, ranging from liver diseases that display keratin accumulations (called Mallory bodies),24 Alexander disease with glial fibrillary acidic protein (GFAP) accumulations (called Rosenthal fibers)25 and a whole host of diseases in the nervous system including Alzheimer disease, Parkinson disease, Charcot-Marie-Tooth disease and many others that have neuro- IF accumulations.26,27 Understanding GAN, albeit an extremely rare disease, might well lead to the clues required to truly understand these various disorders. It should also be noted that very little is known about the normal turnover of IF proteins in general, so GAN has already spun off an exciting new insight into the turnover and degradation of several types of IF proteins long thought to assemble into one of the most stable cytoskeletal networks in vertebrate cells. Finally, our findings raise the possibility that one therapeutic avenue for GAN and related diseases might be to deliver wild-type GAN or to screen for small molecules that take apart the large aggregates of IF. This overexpression should remove aggregates of IF not only in fibroblasts, but also in neurons, allowing the free movement of organelles, such as mitochondria (Fig. 2).


Explaining intermediate filament accumulation in giant axonal neuropathy.

Opal P, Goldman RD - Rare Dis (2013)

Figure 2. Gigaxonin overexpression clears IF in fibroblasts (A) and neurons (B). In neurons this is likely to lead to improvement of axonal transport of organelles such as mitochondria as they are no longer hindered by IF aggregation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927486&req=5

Figure 2: Figure 2. Gigaxonin overexpression clears IF in fibroblasts (A) and neurons (B). In neurons this is likely to lead to improvement of axonal transport of organelles such as mitochondria as they are no longer hindered by IF aggregation.
Mentions: Despite numerous unanswered questions, we believe that our results convincingly demonstrate that gigaxonin is an important player in the degradation of IF. Clearly, this is an important insight for GAN. We speculate that gigaxonin might play a much broader role in a number of diseases where IF accumulate, ranging from liver diseases that display keratin accumulations (called Mallory bodies),24 Alexander disease with glial fibrillary acidic protein (GFAP) accumulations (called Rosenthal fibers)25 and a whole host of diseases in the nervous system including Alzheimer disease, Parkinson disease, Charcot-Marie-Tooth disease and many others that have neuro- IF accumulations.26,27 Understanding GAN, albeit an extremely rare disease, might well lead to the clues required to truly understand these various disorders. It should also be noted that very little is known about the normal turnover of IF proteins in general, so GAN has already spun off an exciting new insight into the turnover and degradation of several types of IF proteins long thought to assemble into one of the most stable cytoskeletal networks in vertebrate cells. Finally, our findings raise the possibility that one therapeutic avenue for GAN and related diseases might be to deliver wild-type GAN or to screen for small molecules that take apart the large aggregates of IF. This overexpression should remove aggregates of IF not only in fibroblasts, but also in neurons, allowing the free movement of organelles, such as mitochondria (Fig. 2).

Bottom Line: Although a range of cell types are affected in GAN, neurons display the most severe pathology, with neuronal intermediate filament accumulation and aggregation; this in turn causes axonal swellings or "giant axons." A mechanistic understanding of GAN IF pathology has eluded researchers for many years.In a recent study(1) we demonstrate that the normal function of gigaxonin is to regulate the degradation of IF proteins via the proteasome.Our findings present the first direct link between GAN mutations and IF pathology; moreover, given the importance of IF aggregations in a wide range of disease conditions, our findings could have wider ramifications.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell and Molecular Biology; Northwestern University Feinberg School of Medicine; Chicago, IL USA ; Davee Department of Neurology; Northwestern University Feinberg School of Medicine; Chicago, IL USA.

ABSTRACT
Giant axonal neuropathy (GAN)(1) is a rare autosomal recessive neurological disorder caused by mutations in the GAN gene that encodes gigaxonin, a member of the BTB/Kelch family of E3 ligase adaptor proteins.(1) This disease is characterized by the aggregation of Intermediate Filaments (IF)-cytoskeletal elements that play important roles in cell physiology including the regulation of cell shape, motility, mechanics and intra-cellular signaling. Although a range of cell types are affected in GAN, neurons display the most severe pathology, with neuronal intermediate filament accumulation and aggregation; this in turn causes axonal swellings or "giant axons." A mechanistic understanding of GAN IF pathology has eluded researchers for many years. In a recent study(1) we demonstrate that the normal function of gigaxonin is to regulate the degradation of IF proteins via the proteasome. Our findings present the first direct link between GAN mutations and IF pathology; moreover, given the importance of IF aggregations in a wide range of disease conditions, our findings could have wider ramifications.

No MeSH data available.


Related in: MedlinePlus