Neurofilament dynamics and involvement in neurological disorders

Gentil, Benoît J.; Tibshirani, Michael; Durham, Heather D.

doi:10.1007/s00441-014-2082-7

Cited by 82 publications

(81 citation statements)

References 156 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Axonal transport defects also play a role in neurodegeneration [88–91]. KIF5B, which codes for kinesin (anterograde), DYNCL1, which codes for dynein (retrograde) and MAPT (tau, a microtubule associated protein) were significantly increased with E treatment in old chow-fed monkeys, but not in WSD-fed monkeys.…”

Section: Discussionmentioning

confidence: 99%

Effects of obesogenic diet and estradiol on dorsal raphe gene expression in old female macaques

et al. 2017

View full text Add to dashboard Cite

The beneficial effects of bioidentical ovarian steroid hormone therapy (HT) during the perimenopause are gaining recognition. However, the positive effects of estrogen (E) plus or minus progesterone (P) administration to ovariectomized (Ovx) lab animals were recognized in multiple systems for years before clinical trials could adequately duplicate the results. Moreover, very large numbers of women are often needed to find statistically significant results in clinical trials of HT; and there are still opposing results being published, especially in neural and cardiovascular systems. One of the obvious differences between human and animal studies is diet. Laboratory animals are fed a diet that is low in fat and refined sugar, but high in micronutrients. In the US, a large portion of the population eats what is known as a “western style diet” or WSD that provides calories from 36% fat, 44% carbohydrates (includes 18.5% sugars) and 18% protein. Unfortunately, obesity and diabetes have reached epidemic proportions and the percentage of obese women in clinical trials may be overlooked. We questioned whether WSD and obesity could decrease the positive neural effects of estradiol (E) in the serotonin system of old macaques that were surgically menopausal. Old ovo-hysterectomized female monkeys were fed WSD for 2.5 years, and treated with placebo, Immediate E (ImE) or Delayed E (DE). Compared to old Ovx macaques on primate chow and treated with placebo or E, the WSD-fed monkeys exhibited greater individual variance and blunted responses to E-treatment in the expression of genes related to serotonin neurotransmission, CRH components in the midbrain, synapse assembly, DNA repair, protein folding, ubiquitylation, transport and neurodegeneration. For many of the genes examined, transcript abundance was lower in WSD-fed than chow-fed monkeys. In summary, an obesogenic diet for 2.5 years in old surgically menopausal macaques blunted or increased variability in E-induced gene expression in the dorsal raphe. These results suggest that with regard to function and viability in the dorsal raphe, HT may not be as beneficial for obese women as normal weight women.

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of obesogenic diet and estradiol on dorsal raphe gene expression in old female macaques

et al. 2017

View full text Add to dashboard Cite

show abstract

“…6,7 Several studies have shown elevated levels of NfL in the CSF of patients suffering from neurodegenerative conditions. [7][8][9] Further, CSF NfL levels seem to reflect progression of various neurological conditions, including multiple sclerosis and neurodegenerative dementia disorders. 10,11 Ultrasensitive methods have enabled the quantification of NfL in serum.…”

Section: Introductionmentioning

confidence: 99%

Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson’s Disease Progression

Mollenhauer

Dakna

Liu

et al. 2019

Preprint

View full text Add to dashboard Cite

Background: Alterations in neurofilament light chain (NfL), reflecting axonal damage, have been proposed as a biomarker for neurological disorders including Parkinson's disease (PD). Methods:We measured NfL concentrations by immunoassay in (1) a set of longitudinal CSF samples from 82 PD, 14 other neurodegenerative disorders (OND), and 53 healthy controls (HC);(2) A cross-sectional cohort with paired CSF and serum samples from subjects with 151 PD, 344 OND, and 20 HC, and (3a) a large longitudinal validation cohort with serum samples from 375 PD, 178 HC, and 57 prodromal Lewy Body disorder with hyposmia or isolated REM sleep behaviour disorder (iRBD), (3b) 216 symptomatic and 298 asymptomatic LRRK2, GBA, and SNCA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI). Mean differences in serum NfL levels between diagnostic groups, and correlation with motor signs, cognitive measures and dopamine transporter imaging, were assessed. Linear mixed effects models were used to assess longitudinal changes in log10 (NfL) in relation to demographic, clinical, and imaging variables. Findings:In the longitudinal cohort (1) NfL in CSF increased over time and was significantly positively correlated with MDS-UPDRS III motor and total scores in the PD group (p=0·0231 and 0·0081). In the cross-sectional cohort (2) the paired CSF and serum NfL samples were highly correlated (Spearman's rank ߩ ො ൌ 0 7 3 ; p<10^-6). In the large validation cohort (3a) mean baseline serum NfL was higher in PD (13 ±7·2pg/ml), hyposmics (15±15·1pg/ml), and iRBD (17±8pg/ml) compared with HC (12±6·7pg/ml) but was highest in the seven OND cases (18±7pg/ml). In the genetic cohort (3b), serum NfL levels were lower in asymptomatic than in symptomatic mutation carriers. There was a significant (age-adjusted) longitudinal increase in serum NfL in PD compared with HC. Serum NfL values were significantly positively associated with longitudinal MDS-UPDRS motor and total scores, as well as age. Interpretation: We identified NfL as the first blood-based PD progression biomarker. NfL levels in serum samples are increased in PD compared to HC, increase significantly over time in PD, and correlate with a clinical measure of disease severity. Although the specificity of NfL in PD is low and additional, more specific biomarkers are needed, serum NfL is the first blood-based biomarker candidate that could support disease stratification (PD vs. OND), track clinical progression, and might be used to assess responsiveness to neuroprotective treatments. M o l l e n h a u e r 5Neurofilaments are highly phosphorylated neuronal cytoskeleton components composed of three subunits of differing molecular weight maintaining neuronal structure and determining axonal calibre. The 68 kDa neurofilament light chain (NfL) is essential for the assembly of the complex as it forms its backbone and is released into extracellular fluids in response to axonal damage. 6,7 Several studies have shown elevated levels of NfL in the CSF of patients suffering from neurodegenerativ...

show abstract

“…To evaluate assembly properties, the constructs were expressed in SW13 vim-cells, which lack endogenous intermediate filament proteins. In mammalian cells, NEFL dimerizes with NEFM and NEFH and is a core protein necessary for the assembly of NF proteins into filamentous structures [61]. In order to determine the assembly competency of neflb variants, eGFP-neflbE4 or eGFP-neflbE3 were expressed alone or in combination with mouse NEFM or NEFH ( Figure 5A).…”

Section: Facsmentioning

confidence: 99%

Functional characterization of Neurofilament Light b splicing andmisbalance in zebrafish

Demy

Campanari

Munoz-Ruiz

et al. 2020

Preprint

View full text Add to dashboard Cite

Neurofilaments (NFs), a major cytoskeletal component of motor neurons, play a key role in their differentiation, establishment and maintenance of their morphology and mechanical strength. The de novo assembly of these neuronal intermediate filaments requires the presence of the neurofilament light subunit, NEFL, which expression is reduced in motor neurons in Amyotrophic Lateral Sclerosis (ALS). This study used zebrafish as a model to characterize the NEFL homologue neflb, which encodes two different isoforms via splicing of the primary transcript (neflbE4 and neflbE3). In vivo imaging showed that neflb is crucial for proper neuronal development, and that disrupting the balance between its two isoforms specifically affects NF assembly and motor axon growth, with resulting motor deficits. This equilibrium is also disrupted upon partial depletion of TDP-43, a RNA binding protein that is mislocalized into cytoplasmic inclusions in ALS. The study supports interaction of NEFL expression and splicing with TDP-43 in a common pathway, both biologically and pathogenetically.

show abstract

Neurofilament dynamics and involvement in neurological disorders

Cited by 82 publications

References 156 publications

Effects of obesogenic diet and estradiol on dorsal raphe gene expression in old female macaques

Effects of obesogenic diet and estradiol on dorsal raphe gene expression in old female macaques

Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson’s Disease Progression

Functional characterization of Neurofilament Light b splicing andmisbalance in zebrafish

Contact Info

Product

Resources

About