PFN1 mutations are rare in Han Chinese populations with amyotrophic lateral sclerosis

Chen, Yongping; Zheng, Zhenzhen; Huang, Rui; Chen, Ke; Song, Wei; Zhao, Bi; Chen, Xueping; Yang, Yuan; Yuan, Li-Xing

doi:10.1016/j.neurobiolaging.2013.01.013

Cited by 45 publications

(37 citation statements)

References 42 publications

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“…Thus, neither canonical binding site is required for MT interactions. This led us to consider whether surfaces on Profilin mutated in ALS might be involved in regulating MT dynamics [5,6]. The ALS-linked mutations in PFN1 are dominant in patients, and their expression over endogenous PFN1 in cultured primary neurons results in ALS-like phenotypes, including increased stress granule formation [22], impaired neurite outgrowth [5,7], and motor neuron degeneration [7].…”

Section: Resultsmentioning

confidence: 99%

“…However, Profilin also influences microtubule dynamics in cells, which may be mediated in part through its interactions with Formins that in turn bind microtubules [3,4]. Specific residues on human Profilin-1 (PFN1) are mutated in patients with amyotrophic lateral sclerosis (ALS) [5,6]. However, the observation that some ALS-linked PFN1 mutants fail to alter cellular actin organization or dynamics [5–8] or in vitro actin-monomer affinity [9] has been perplexing, given that Profilin is best understood as an actin regulator.…”

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confidence: 99%

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Profilin Directly Promotes Microtubule Growth through Residues Mutated in Amyotrophic Lateral Sclerosis

2017

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SUMMARY Profilin is an abundant actin monomer binding protein with critical actin regulatory roles in vivo [1,2]. However, Profilin also influences microtubule dynamics in cells, which may be mediated in part through its interactions with Formins that in turn bind microtubules [3,4]. Specific residues on human Profilin-1 (PFN1) are mutated in patients with amyotrophic lateral sclerosis (ALS) [5,6]. However, the observation that some ALS-linked PFN1 mutants fail to alter cellular actin organization or dynamics [5–8] or in vitro actin-monomer affinity [9] has been perplexing, given that Profilin is best understood as an actin regulator. Here, we investigated direct effects of Profilin on microtubule dynamics, and whether ALS-linked mutations in PFN1 disrupt such functions. We found that human, fly, and yeast Profilin homologs all directly enhance microtubule growth rate by several-fold in vitro. Microtubule stimulatory effects were unaffected by mutations in the canonical actin- or poly-proline-binding sites of Profilin. Instead, microtubule activities depended on specific surface residues on Profilin mutated in ALS patients. Further, microtubule effects were attenuated by increasing concentrations of actin monomers, suggesting competition between actin and microtubules for binding Profilin. Consistent with these biochemical observations, a two-fold increase in the expression level of wildtype PFN1, but not the ALS-linked PFN1 mutants, increased microtubule growth rates in cells. Together, these results demonstrate that Profilin directly enhances the growth rate of microtubules. Further, they suggest that ALS-linked mutations in PFN1 may perturb cellular microtubule dynamics, and/or the coordination between the actin and microtubule cytoskeletons, leading to motor neuron degeneration.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Profilin Directly Promotes Microtubule Growth through Residues Mutated in Amyotrophic Lateral Sclerosis

2017

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“…PFN1, HNRNPA1, CHCHD10, MATR3, TBK1, TUBA4A and CCNF were identified disease-causing one after another based on the analysis of WES performed in several ALS families or large cohorts of familial and sporadic ALS cases with Caucasian origin (Bannwarth et al, 2014; Cirulli et al, 2015; Freischmidt et al, 2015; Johnson et al, 2014; Kim et al, 2013, 2016; Smith et al, 2014; Wu et al, 2012). Unfortunately, mutations in above-mentioned genes are quite rare in Chinese population, suggesting genes may not be informative of the genetics in Chinese ALS patients (Chen et al, 2013; Li et al, 2016; Lin et al, 2015; Pan et al, 2017; Shen et al, 2017; Shu et al, 2016; Soong et al, 2014; Tsai et al, 2016, 2017; Xu et al, 2016; Zhou et al, 2017; Zou et al, 2013c). Targeted next-generation sequencing (NGS), a cost-effective approach for variant screening in known ALS genes, has been applied primarily in fALS and jALS (Liu et al, 2014b, 2017b).…”

Section: Genetic Characteristics Of Chinese Als Patientsmentioning

confidence: 99%

The epidemiology and genetics of Amyotrophic lateral sclerosis in China

Liu

Gao

et al. 2018

Brain Research

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with loss of motor neurons. Previous knowledge of the disease has been mainly based on studies from Caucasian ALS patients of European descent. Here we review the epidemiological characteristics of ALS among the Chinese population in order to compare the similarities and differences between Chinese ALS cases and those from other countries. We describe a potential lower incidence and prevalence of ALS, a younger age of onset and a lower proportion of familial ALS cases in the Chinese population. Additionally, we highlight potential genetic differences between Chinese and Caucasian ALS patients. Most notably, the frequency of GGGGCC repeat expansions in C9ORF72 in Chinese ALS is significantly lower than in Caucasians. Since some conclusions might not be consistent across all of the studies around China to date, we suggest that it is necessary to carry out a prospective population-based study and large-scale gene sequencing around to better define epidemiological and genetic features of Chinese ALS patients.

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“…All the PFN1 mutants produce ubiquitinated, insoluble aggregates except E117G (Wu et al, 2012), which may be a risk factor rather than a causative mutation (Fratta et al, 2014). In addition to the first four mutations discovered, a rare, non-synonymous mutation (R136W) was subsequently identified in a Chinese population (Chen et al, 2013) and a novel phosphorylation site mutation (T109M) was discovered in a large screen of US, Nordic, and German ALS/FTD cohorts (Ingre et al, 2013). In contrast, PFN1 mutations are not common in Australian ALS/FTD cohorts (Yang et al, 2013).…”

Section: Profilinmentioning

confidence: 99%

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

Shahheydari

Ragagnin

Walker

et al. 2017

Front. Mol. Neurosci.

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Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER)-associated degradation (ERAD) and the formation of stress granules (SGs), to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that are now recognized to overlap clinically and pathologically, forming a continuous disease spectrum. In this review article, we detail the evidence for dysregulation of protein quality control mechanisms across the whole ALS-FTD continuum, by discussing the major proteins implicated in ALS and/or FTD. We also discuss possible ways in which protein quality mechanisms could be targeted therapeutically in these disorders and highlight promising protein quality control-based therapeutics for clinical trials.

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PFN1 mutations are rare in Han Chinese populations with amyotrophic lateral sclerosis

Cited by 45 publications

References 42 publications

Profilin Directly Promotes Microtubule Growth through Residues Mutated in Amyotrophic Lateral Sclerosis

Profilin Directly Promotes Microtubule Growth through Residues Mutated in Amyotrophic Lateral Sclerosis

The epidemiology and genetics of Amyotrophic lateral sclerosis in China

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

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