Phosphorylation of Neurofilaments Is Altered in Amyotrophic Lateral Sclerosis

Manetto, Valeria; Sternberger, Nancy H.; Perry, George; Sternberger, Ludwig A.; Gambetti, P

doi:10.1097/00005072-198811000-00007

Cited by 188 publications

(77 citation statements)

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“…Aberrant accumulation of pNF in axonal swellings and somas has been a hallmark of axonal transport disruption in neurodegenerative diseases (Manetto et al, 1988;Munoz et al, 1988;Mizusawa et al, 1989;Sobue et al, 1990;Rouleau et al, 1996;Stokin et al, 2005). Because phosphorylation of neurofilaments has been shown to de- crease active transport of neurofilaments through retinal axons (Jung and Shea, 1999), it is possible that excess pNF within intraocular axons may itself cause progressive declines in RGC gene expression and retrograde transport.…”

Section: Discussionmentioning

confidence: 99%

Retinal Ganglion Cells Downregulate Gene Expression and Lose Their Axons within the Optic Nerve Head in a Mouse Glaucoma Model

Soto¹,

Oglesby²,

Buckingham³

et al. 2008

J. Neurosci.

258

236

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Little is known about molecular changes occurring within retinal ganglion cells (RGCs) before their death in glaucoma. Taking advantage of the fact that ␥-synuclein (Sncg) mRNA is expressed specifically and highly in adult mouse RGCs, we show in the DBA/2J mouse model of glaucoma that there is not only a loss of cells expressing this gene, but also a downregulation of gene expression of Sncg and many other genes within large numbers of RGCs. This downregulation of gene expression within RGCs occurs together with reductions in FluoroGold (FG) retrograde transport. Surprisingly, there are also large numbers of Sncg-expressing cells without any FG labeling, and among these many that have a marker previously associated with disconnected RGCs, accumulation of phosphorylated neurofilaments in their somas. These same diseased retinas also have large numbers of RGCs that maintain the intraocular portion while losing the optic nerve portion of their axons, and these disconnected axons terminate within the optic nerve head. Our data support the view that RGC degeneration in glaucoma has two separable stages: the first involves atrophy of RGCs, whereas the second involves an insult to axons, which causes the degeneration of axon portions distal to the optic nerve head but does not cause the immediate degeneration of intraretinal portions of axons or the immediate death of RGCs.

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Section: Discussionmentioning

confidence: 99%

Retinal Ganglion Cells Downregulate Gene Expression and Lose Their Axons within the Optic Nerve Head in a Mouse Glaucoma Model

Soto¹,

Oglesby²,

Buckingham³

et al. 2008

J. Neurosci.

258

236

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“…In Parkinson's disease (PD) and dementia with Lewy bodies (DLB), α-internexin and NF triplet proteins are found in a subset of α-synuclein-positive Lewy bodies, although their role in lesion formation or neurodegeneration is uncertain [53,54]. In ALS, abnormal accumulations of phosphorylated NF proteins are present in the perikaryon of affected neurons, swollen axons, and spheroids, although the significance of the phosphorylation of NF proteins within the cytoplasm is unclear [49,55,56]. However, abnormal phosphorylation may impede axonal transport and contribute to neuronal dysfunction, while constitutive phosphorylation of NFs may protect them against proteolysis [57].…”

Section: Neuronal Ifs and Diseasementioning

confidence: 99%

The cytoskeleton in neurodegenerative diseases

Cairns

Lee

Trojanowski

2004

The Journal of Pathology

165

114

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In vitro and transgenic animal models are being used to demonstrate that different mutations impair protein function, promote tau fibrilization, or perturb tau gene splicing, leading to aberrant and distinct tau aggregates. For recognition of these disorders at neuropathological examination, immunohistochemistry is needed, and this may be combined with biochemistry and molecular genetics to properly determine the nosology of a particular case. As reviewed here, the identification of molecular genetic defects and biochemical alterations in cytoskeletal proteins of human neurodegenerative diseases has facilitated experimental studies and will promote the development of assays of molecules which inhibit abnormal neuronal IF and tau protein inclusions.

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“…Recently, we described α-internexin as a major component of the pathological hallmark of NIFID [5]. Although previous studies have demonstrated the co-localization of NF epitopes in AD, PD, DLB, and MND [19,25,26,28,29,32,33,34,35], no study has demonstrated the presence of α-internexin as a component of the pathological inclusions of any neurodegenerative disease other than NIFID.…”

Section: Introductionmentioning

confidence: 99%

“…The use of phosphorylation-dependent and -independent antibodies to NF epitopes has enabled the immunohistochemical dissection of these proteins and has revealed that NFs within the perikaryon and proximal segments of axons and dendrites are normally hypophosphorylated, while NFs in axons are heavily phosphorylated. In neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB) and motor neuron disease (MND), abnormal accumulations of phosphorylated NF proteins in the cell body have been reported [19,26,28,29,32,33,34,35], although the significance of the phosphorylation of NF proteins within the cytoplasm is unclear. However, abnormal phosphorylation may impede axonal transport and contribute to neuronal dysfunction, while constitutive phosphorylation of NFs may protect them against proteolysis [17].…”

Section: Introductionmentioning

confidence: 99%

?-Internexin aggregates are abundant in neuronal intermediate filament inclusion disease (NIFID) but rare in other neurodegenerative diseases

et al. 2004

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Abnormal neuronal aggregates of α-internexin and the three neurofilament (NF) subunits, NF-L, NF-M, and NF-H have recently been identified as the pathological hallmarks of neuronal intermediate filament (IF) inclusion disease (NIFID), a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal and extrapyramidal signs. α-Internexin, a class IV IF protein, a major component of inclusions in NIFID, has not previously been identified as a component of the pathological protein aggregates of any other neurodegenerative disease. Therefore, to determine the specificity of this protein, α-internexin immunohistochemistry was undertaken on cases of NIFID, non-tau frontotemporal

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Phosphorylation of Neurofilaments Is Altered in Amyotrophic Lateral Sclerosis

Cited by 188 publications

References 0 publications

Retinal Ganglion Cells Downregulate Gene Expression and Lose Their Axons within the Optic Nerve Head in a Mouse Glaucoma Model

Retinal Ganglion Cells Downregulate Gene Expression and Lose Their Axons within the Optic Nerve Head in a Mouse Glaucoma Model

The cytoskeleton in neurodegenerative diseases

?-Internexin aggregates are abundant in neuronal intermediate filament inclusion disease (NIFID) but rare in other neurodegenerative diseases

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