A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement.

Mitochondrial DNA instability disorders are responsible for a large clinical spectrum, among which amyotrophic lateral sclerosis-like symptoms and frontotemporal dementia are extremely rare. We report a large family with a late-onset phenotype including motor neuron disease, cognitive decline resembling frontotemporal dementia, cerebellar ataxia and myopathy. In all patients, muscle biopsy showed ragged-red and cytochrome c oxidase-negative fibres with combined respiratory chain deficiency and abnormal assembly of complex V. The multiple mitochondrial DNA deletions found in skeletal muscle revealed a mitochondrial DNA instability disorder. Patient fibroblasts present with respiratory chain deficiency, mitochondrial ultrastructural alterations and fragmentation of the mitochondrial network. Interestingly, expression of matrix-targeted photoactivatable GFP showed that mitochondrial fusion was not inhibited in patient fibroblasts. Using whole-exome sequencing we identified a missense mutation (c.176C>T; p.Ser59Leu) in the CHCHD10 gene that encodes a coiled-coil helix coiled-coil helix protein, whose function is unknown. We show that CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Overexpression of a CHCHD10 mutant allele in HeLa cells led to fragmentation of the mitochondrial network and ultrastructural major abnormalities including loss, disorganization and dilatation of cristae. The observation of a frontotemporal dementia-amyotrophic lateral sclerosis phenotype in a mitochondrial disease led us to analyse CHCHD10 in a cohort of 21 families with pathologically proven frontotemporal dementia-amyotrophic lateral sclerosis. We identified the same missense p.Ser59Leu mutation in one of these families. This work opens a novel field to explore the pathogenesis of the frontotemporal dementia-amyotrophic lateral sclerosis clinical spectrum by showing that mitochondrial disease may be at the origin of some of these phenotypes

Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD

Forkhead pathway in the control of adult neurogenesis.

Abstract New cells are continuously generated from immature proliferating cells in the adult brain in two neurogenic niches known as the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ) of the lateral ventricles. However, the molecular mechanisms regulating their proliferation, differentiation, migration and functional integration of newborn neurons in pre-existing neural network remain largely unknown. Forkhead box (Fox) proteins belong to a large family of transcription factors implicated in a wide variety of biological processes. Recently, there has been accumulating evidence that several members of this family of proteins play important roles in adult neurogenesis. Here, we describe recent advances in our understanding of regulation provided by Fox factors in adult neurogenesis, and evaluate the potential role of Fox proteins as targets for therapeutic intervention in neurodegenerative diseases. Stem Cells  2014;32:1398–1407</jats:p

Double Trouble Mutations Underlie Mitochondrial Dynamics Disorders in a Severe Form of Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease type 2A (CMT2A) is an inherited axonal peripheral neuropathy mainly caused by mutations in the mitofusin 2 (MFN2) gene encoding for the MFN2 protein, a GTPase involved in the mitochondrial dynamics and bioenergetics. We identified a novel mutation, that was inherited from her mother, in the MFN2 protein (Met234Ile) in a Charcot-Marie-Tooth patient. She has also a variant of uncertain significance (Thr36Ala), in the PMP22 gene, encoding for peripheral myelin protein 22, inherited from her father. The patient presented severe sensorimotor neuropathy with early onset. The mother presented a distal muscle atrophy in the legs, the father was asymptomatic. To show the pathogenicity of these mutations, we characterized the structure, adenosine triphosphate (ATP) content, bioelectric characteristics and functions of mitochondria in cultured primary fibroblasts obtained from the proband and her parents. Under normal culture conditions, mitochondria showed normal morphology. Under oxidative stress conditions, ATP production was reduced and the proband cells showed a decrease of the mitochondrial fusion with small connected networks and a decrease of the mitochondrial volume. The alteration of the mitochondrial network only when cells are challenged in aerobiosis testifies to the fragility of mitochondria, which are unable to meet the metabolic needs of neurons. Interestingly, fibroblasts derived from the two parents did not show any change. These results support the hypothesis that the mutation in the MFN2 gene altering mitochondrial bioenergetics and fusion causes axonal sensorymotor neuropathy. We speculate that PMP22 may promote mitochondrial dysfunction, myelin having a role in mitochondrial metabolism

Loss of MICOS complex integrity and mitochondrial damage, but not TDP-43 mitochondrial localisation, are likely associated with severity of CHCHD10-related diseases

Following the involvement of CHCHD10 in FrontoTemporal-Dementia-Amyotrophic Lateral Sclerosis (FTD-ALS) clinical spectrum, a founder mutation (p.Gly66Val) in the same gene was identified in Finnish families with late onset spinal motor neuronopathy (SMAJ). SMAJ is a slowly progressive form of spinal muscular atrophy with a life expectancy within normal range. In order to understand why the p.Ser59Leu mutation, responsible for severe FTD-ALS, and the p.Gly66Val mutation could lead to different levels of severity, we compared their effects in patient cells. Unlike affected individuals bearing the p.Ser59Leu mutation, patients presenting with SMAJ phenotype have neither mitochondrial myopathy nor mtDNA instability. The expression of CHCHD10(S59L) mutant allele leads to disassembly of mitochondrial contact site and cristae organizing system (MICOS) with mitochondria] dysfunction and loss of cristae in patient fibroblasts. We also show that G66V fibroblasts do not display the loss of MICOS complex integrity and mitochondrial damage found in S59L cells. However, S59L and G66V fibroblasts show comparable accumulation of phosphorylated mitochondrial TDP-43 suggesting that the severity of phenotype and mitochondrial damage do not depend on mitochondrial TDP-43 localization. The expression of the CHCHD10(G66V) allele is responsible for mitochondrial network fragmentation and decreased sensitivity towards apoptotic stimuli, but with a less severe effect than that found in cells expressing the CHCHD10(S59L) allele. Taken together, our data show that cellular phenotypes associated with p.Ser59Leu and p.Gly66Val mutations in CHCHD10 are different; loss of MICOS complex integrity and mitochondrial dysfunction, but not TDP-43 mitochondrial localization, being likely essential to develop a severe motor neuron disease.Peer reviewe

LXR antagonists induce ABCD2 expression

X-linked adrenoleukodystrophy (X-ALD) is a rare neurodegenerative disorder characterized by the accumulation of very-long-chain fatty acids resulting from a β-oxidation defect. Oxidative stress and inflammation are also key components of the pathogenesis. X-ALD is caused by mutations in the ABCD1 gene, which encodes for a peroxisomal half ABC transporter predicted to participate in the entry of VLCFA-CoA into the peroxisome, the unique site of their β-oxidation. Two homologous peroxisomal ABC transporters, ABCD2 and ABCD3 have been proven to compensate for ABCD1 deficiency when overexpressed. Pharmacological induction of these target genes could therefore represent an alternative therapy for X-ALD patients. Since LXR activation was shown to repress ABCD2 expression, we investigated the effects of LXR antagonists in different cell lines. Cells were treated with GSK(17) (a LXR antagonist recently discovered from the GlaxoSmithKline compound collection), 22(S)-hydroxycholesterol (22S-HC, another LXR antagonist) and 22R-HC (an endogenous LXR agonist). We observed up-regulation of ABCD2, ABCD3 and CTNNB1 (the gene encoding for β-catenin, which was recently demonstrated to induce ABCD2 expression) in human HepG2 hepatoma cells and in X-ALD skin fibroblasts treated with LXR antagonists. Interestingly, induction in X-ALD fibroblasts was concomitant with a decrease in oxidative stress. Rats treated with 22S-HC showed hepatic induction of the 3 genes of interest. In human, we show by multiple tissue expression array that expression of ABCD2 appears to be inversely correlated with NR1H3 (LXRα) expression. Altogether, antagonists of LXR that are currently developed in the context of dyslipidemia may find another indication with X-ALD

Reply: Are CHCHD10 mutations indeed associated with familial amyotrophic lateral sclerosis?

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Reply: A distinct clinical phenotype in a German kindred with motor neuron disease carrying a CHCHD10 mutation.

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Reply: High prevalence of CHCHD10 mutations in patients with frontotemporal dementia from China.

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Reply: Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease.

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