Neurofilament stoichiometry simulations during neurodegeneration suggest a remarkable self-sufficient and stable in vivo protein structure

Kim, Seonghoon; Chang, Rakwoo; Teunissen, Charlotte E.; Gebremichael, Yeshitila; Petzold, Axel

doi:10.1016/j.jns.2011.04.023

Cited by 21 publications

(20 citation statements)

References 30 publications

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“…4A, red chain) to 70 nm from the core at an ionic strength of 10 mM (Fig. 4B, red chain) (Kim et al, 2011). Additionally, the strong charge repulsive interactions between neighbouring sidearm coronas (Beck et al, 2010) may increase the relative proportion of free protons compared to the non–phosphorylated stage (Figs.…”

Section: Discussionmentioning

confidence: 99%

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Axonal damage in the making: Neurofilament phosphorylation, proton mobility and magnetisation transfer in multiple sclerosis normal appearing white matter

Petzold

Tozer

Schmierer

2011

Experimental Neurology

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AimsMultiple sclerosis (MS) leaves a signature on the phosphorylation and thus proton binding capacity of axonal neurofilament (Nf) proteins. The proton binding capacity in a tissue is the major determinant for exchange between bound and free protons and thus the magnetisation transfer ratio (MTR). This study investigated whether the MTR of non-lesional white matter (NLWM) was related to the brain tissue concentration of neurofilament phosphoforms.MethodsUnfixed post-mortem brain slices of 12 MS patients were analysed using MTR, T1 at 1.5 T. Blocks containing NLWM were processed for embedding in paraffin and inspected microscopically. Adjacent tissue was microdissected, homogenised and specific protein levels were quantified by ELISA for the Nf heavy chain (NfH) phosphoforms, glial fibrillary acidic protein (GFAP), S100B and ferritin.ResultsAveraged hyperphosphorylated NfH (SMI34) but not phosphorylated NfH (SMI35) levels were different between individual patients NLWM. The concentration of hyperphosphorylated NfH-SMI34 correlated with T1 (R = 0.70, p = 0.0114) and — inversely — with MTR (R =−0.73, p = 0.0065). NfH-SMI35 was not correlated to any of the MR indices.ConclusionsPost-translational modifications of axonal proteins such as phosphorylation of neurofilaments occur in NLWM and may precede demyelination. The resulting change of proton mobility influences MTR and T1. This permits the in vivo detection of these subtle tissue changes on a proteomic level in patients with MS.

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Section: Discussionmentioning

confidence: 99%

“…Therefore the T 1 increases and MTR decreases. The protein-structure model is based on in vivo data from patients with multiple sclerosis and was adapted from (Kim et al, 2011). …”

Section: Figmentioning

confidence: 99%

Axonal damage in the making: Neurofilament phosphorylation, proton mobility and magnetisation transfer in multiple sclerosis normal appearing white matter

Petzold

Tozer

Schmierer

2011

Experimental Neurology

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“…Recently, it has been shown that tubuline targeting drugs may preserve microtubule function and protect axons from degradation in models of spinal cord injury [52]. In addition, neurofilaments are in charge of keeping the 3D axonal structure and after damage, neurofilaments become hyperphosphorylated, losing their function and inducing the collapse of axons [53]. Therefore, preserving axonal structure and function is an important strategy for promoting neuroprotection.…”

Section: Neuroprotective Strategiesmentioning

confidence: 99%

Neuroprotective therapies for multiple sclerosis and other demyelinating diseases

Villoslada

2016

Mult Scler Demyelinating Disord

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Damage to the Central Nervous Systems (CNS) in Multiple Sclerosis (MS) seems to be mainly due to chronic inflammation of the CNS with superimposed bouts of inflammatory activity by the adaptive immune system. The immune mediated damage can be amplified by neurodegenerative mechanisms in damaged axons including anterograde or retrograde axonal or transynaptic degeneration, synaptic pruning and neuronal or oligodendrocyte death. As such, it is highly unlikely that CNS damage can be prevented using only immunomodulatory drugs. For this reason, neuroprotection, aimed at preventing axonal, neuronal, myelin, and oligodendrocyte damage and cell death in the presence of this toxic microenvironment is highly pursued in MS and other demyelinating diseases. Neuroprotective strategies target different processes including oxidative stress, ionic imbalance (sodium, potassium or calcium), energy depletion, trophic factor support, metabolites balance, excitotoxicity, apoptosis, remyelination, etc. Although none of these strategies have translated into approved drugs to date, improvement in the understanding of underlying biology, in the design of clinical trials specific for assessing neuroprotection, and new technologies for developing novel therapies for neuroprotection suggest a new avenue for treating MS, Optic Neuritis or Neuromyelitis Optica (NMO). Several of these therapies are now entering clinical phases and if successful, such strategies would improve patients' quality of life, and will be even more critical for patients with progressive MS. In the event that such therapies target natural repair mechanisms rather than disease specific processes, they can potentially be useful for other brain diseases such as stroke, neurodegenerative diseases, brain trauma or epilepsy.

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“…NFs are composed of three distinct molecular weight proteins: NF-light (NF-L), NF-medium (NF-M), and NF-heavy (NF-H) [9]. These proteins are under tight stoichiometric balance during the assembly of the NF network [23].…”

Section: Introductionmentioning

confidence: 99%

“…NF-H is a large protein whose tail domain (amino acid residues 502 – 823) includes an estimated 38 – 43 phosphorylation sites, which include but are not limited to 33 non-contiguous lysine-serine-proline repeats [6, 8, 9, 22, 23]. Monoclonal antibodies to SMI-31 react with phosphorylated epitopes on NF-H, although the number and precise distribution of these sites in the tail region of NF-H has not been mapped.…”

Section: Introductionmentioning

confidence: 99%

Neurofilament protein levels: Quantitative analysis in essential tremor cerebellar cortex

Louis

Babij

et al. 2012

Neuroscience Letters

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Essential tremor (ET) is among the most prevalent neurological diseases. A substantial increase in the number of Purkinje cell axonal swellings (torpedoes) has been identified in ET brains. We recently demonstrated that torpedoes in ET contain an over-accumulation of disorganized neurofilament (NF) proteins. This now raises the question whether NF protein composition and/or phosphorylation state in cerebellar tissue might differ between ET cases and controls. We used a Western blot analysis to compare the levels and phosphorylation state of NF proteins and α-internexin in cerebellar tissue from 47 ET cases vs. 26 controls (2:1 ratio). Cases and controls did not differ with respect to the cerebellar levels of NF-light (NF-L), NF-medium (NF-M), NF-heavy (NF-H), or α-internexin. However, SMI-31 levels (i.e., phosphorylated NF-H) and SMI-32 levels (i.e., non-phosphorylated NF-H) were significantly higher in ET cases than controls (1.28 ± 0.47 vs. 1.06 ± 0.32, p = 0.02; and 1.38 ± 0.75 vs. 1.00 ± 0.42, p = 0.006). Whether the abnormal phosphorylation state that we observed is a cause of defective axonal transport and/or function of NFs in ET is not known. NF abnormalities have been demonstrated in several neurodegenerative diseases. Regardless of whether these protein aggregates are the cause or consequence of these diseases, NF abnormalities have been shown to be an important factor in the cellular disruption observed in several neurodegenerative diseases. Therefore, further analyses of these NF abnormalities and their mechanisms are important to enhance our understanding of disease pathogenesis in ET.

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Neurofilament stoichiometry simulations during neurodegeneration suggest a remarkable self-sufficient and stable in vivo protein structure

Cited by 21 publications

References 30 publications

Axonal damage in the making: Neurofilament phosphorylation, proton mobility and magnetisation transfer in multiple sclerosis normal appearing white matter

Axonal damage in the making: Neurofilament phosphorylation, proton mobility and magnetisation transfer in multiple sclerosis normal appearing white matter

Neuroprotective therapies for multiple sclerosis and other demyelinating diseases

Neurofilament protein levels: Quantitative analysis in essential tremor cerebellar cortex

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