Parkinson's disease (PD) is a common motor disorder of mysterious etiology. It is due to the progressive degeneration of the dopaminergic neurons of the substantia nigra and is accompanied by the ...appearance of intraneuronal inclusions enriched in α-synuclein, the Lewy bodies. It is becoming increasingly clear that genetic factors contribute to its complex pathogenesis. Over the past decade, the genetic basis of rare PD forms with Mendelian inheritance, representing no more than 10% of the cases, has been investigated. More than 16 loci and 11 associated genes have been identified so far; genome-wide association studies have provided convincing evidence that polymorphic variants in these genes contribute to sporadic PD. The knowledge acquired of the functions of their protein products has revealed pathways of neurodegeneration that may be shared between inherited and sporadic PD. An impressive set of data in different model systems strongly suggest that mitochondrial dysfunction plays a central role in clinically similar, early-onset autosomal recessive PD forms caused by parkin and PINK1, and possibly DJ-1 gene mutations. In contrast, α-synuclein accumulation in Lewy bodies defines a spectrum of disorders ranging from typical late-onset PD to PD dementia and including sporadic and autosomal dominant PD forms due to mutations in SCNA and LRRK2. However, the pathological role of Lewy bodies remains uncertain, as they may or may not be present in PD forms with one and the same LRRK2 mutation. Impairment of autophagy-based protein/organelle degradation pathways is emerging as a possible unifying but still fragile pathogenic scenario in PD. Strengthening these discoveries and finding other convergence points by identifying new genes responsible for Mendelian forms of PD and exploring their functions and relationships are the main challenges of the next decade. It is also the way to follow to open new promising avenues of neuroprotective treatment for this devastating disorder.
Objective
To define the role that repeat expansions of a GGGGCC hexanucleotide sequence of the C9orf72 gene play in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar ...degeneration (FTLD). A genetic model for ALS was developed to determine whether loss of function of the zebrafish orthologue of C9orf72 (zC9orf72) leads to abnormalities in neuronal development.
Methods
C9orf72 mRNA levels were quantified in brain and lymphoblasts derived from FTLD and ALS/FTLD patients and in zebrafish. Knockdown of the zC9orf72 was performed using 2 specific antisense morpholino oligonucleotides to block transcription. Quantifications of spontaneous swimming and tactile escape response, as well as measurements of axonal projections from the spinal cord, were performed.
Results
Significantly decreased expression of C9orf72 transcripts in brain and lymphoblasts was found in sporadic FTLD and ALS/FTLD patients with normal‐size or expanded hexanucleotide repeats. The zC9orf72 is selectively expressed in the developing nervous system at developmental stages. Loss of function of the zC9orf72 transcripts causes both behavioral and cellular deficits related to locomotion without major morphological abnormalities. These deficits were rescued upon overexpression of human C9orf72 mRNA transcripts.
Interpretation
Our results indicate C9orf72 haploinsufficiency could be a contributing factor in the spectrum of ALS/FTLD neurodegenerative disorders. Loss of function of the zebrafish orthologue of zC9orf72 expression in zebrafish is associated with axonal degeneration of motor neurons that can be rescued by expressing human C9orf72 mRNA, highlighting the specificity of the induced phenotype. These results reveal a pathogenic consequence of decreased C9orf72 levels, supporting a loss of function mechanism of disease. Ann Neurol 2013;74:180–187
Autosomal recessive early-onset Parkinson's disease is most often caused by mutations in the genes encoding the cytosolic E3 ubiquitin ligase Parkin and the mitochondrial serine/threonine kinase ...PINK1. Studies in Drosophila models and mammalian cells have demonstrated that these proteins regulate various aspects of mitochondrial physiology, including organelle transport, dynamics and turnover. How PINK1 and Parkin orchestrate these processes, and whether they always do so within a common pathway remain to be clarified.
We have revisited the role of PINK1 and Parkin in mitochondrial dynamics, and explored its relation to the mitochondrial clearance program controlled by these proteins. We show that PINK1 and Parkin promote Drp1-dependent mitochondrial fission by mechanisms that are at least in part independent. Parkin-mediated mitochondrial fragmentation was abolished by treatments interfering with the calcium/calmodulin/calcineurin signaling pathway, suggesting that it requires dephosphorylation of serine 637 of Drp1. Parkinson's disease-causing mutations with differential impact on mitochondrial morphology and organelle degradation demonstrated that the pro-fission effect of Parkin is not required for efficient mitochondrial clearance. In contrast, the use of Förster energy transfer imaging microscopy revealed that Drp1 and Parkin are co-recruited to mitochondria in proximity of PINK1 following mitochondrial depolarization, indicating spatial coordination between these events in mitochondrial degradation. Our results also hint at a major role of the outer mitochondrial adaptor MiD51 in Drp1 recruitment and Parkin-dependent mitophagy. Altogether, our observations provide new insight into the mechanisms underlying the regulation of mitochondrial dynamics by Parkin and its relation to the mitochondrial clearance program mediated by the PINK1/Parkin pathway.
•Parkin promotes mitochondrial fission at least in part independently of PINK1.•Parkin-mediated mitochondrial fission depends on the phosphorylation status of Drp1.•Parkin-mediated mitochondrial fission may not be required for mitochondrial clearance.•PINK1 and Parkin cooperate in mitochondrial Drp1 recruitment prior to mitophagy.
Neurofilament light chain (NfL) is a marker of brain atrophy and predictor of disease progression in rare diseases such as Huntington Disease, but also in more common neurological disorders such as ...Alzheimer's disease. The aim of this study was to measure NfL longitudinally in autosomal dominant spinocerebellar ataxias (SCAs) and establish correlation with clinical and imaging parameters. We enrolled 62 pathological expansions carriers (17 SCA1, 13 SCA2, 19 SCA3, and 13 SCA7) and 19 age-matched controls in a prospective biomarker study between 2011 and 2015 and followed for 24 months at the Paris Brain Institute. We performed neurological examination, brain 3 T MRI and plasma NfL measurements using an ultrasensitive single-molecule array at baseline and at the two-year follow-up visit. We evaluated NfL correlations with ages, CAG repeat sizes, clinical scores and volumetric brain MRIs. NfL levels were significantly higher in SCAs than controls at both time points (p < 0.001). Age-adjusted NfL levels were significantly correlated at baseline with clinical scores (p < 0.01). We identified optimal NfL cut-off concentrations to differentiate controls from carriers for each genotype (SCA1 16.87 pg/mL, SCA2, 19.1 pg/mL, SCA3 16.04 pg/mL, SCA7 16.67 pg/mL). For all SCAs, NfL concentration was stable over two years (p = 0.95) despite a clinical progression (p < 0.0001). Clinical progression between baseline and follow-up was associated with higher NfL concentrations at baseline (p = 0.04). Of note, all premanifest carriers with NfL levels close to cut off concentrations had signs of the disease at follow-up. For all SCAs, the higher the observed NfL, the lower the pons volume at baseline (p < 0.01) and follow-up (p = 0.02). Higher NfL levels at baseline in all SCAs predicted a decrease in cerebellar volume (p = 0.03). This result remained significant for SCA2 only among all genotypes (p = 0.02). Overall, plasma NfL levels at baseline in SCA expansion carriers predict cerebellar volume change and clinical score progression. NfL levels might help refine inclusion criteria for clinical trials in carriers with very subtle signs.
•NfL levels were sustainably higher in SCAs than controls over a two-year period.•Optimal plasma NfL cut-off concentrations was identified for each SCA genotype.•Plasma NfL concentrations predicted cerebellar volume loss at two years in SCAs.•Clinical progression was associated with higher NfL concentrations at baseline.•Premanifest carriers with NfL levels close to cut off had signs of the disease.
Courtin and Brice discuss the paper by Arquivos de Neuro-Psiquiatria, Santos-Lobato and colleagues which offers a systematic review of the literature related to the genetics of Parkinson's Disease ...(PD) in Brazil. It represents the first attempt to gather all the current knowledge on monogenic forms of PD in a large South American country. It is now widely accepted that a substantial proportion of risk for PD is driven by genetics. So far, more than a dozen genes with dominant, recessive or X-linked inheritance have been linked to PD, mostly in familial and/or early onset forms. Another fraction of PD heritability is driven by almost 100 genetic risk factors identified to date.
Neuroinflammation and mitochondrial dysfunction, key mechanisms in the pathogenesis of Parkinson's disease (PD), are usually explored independently. Loss‐of‐function mutations of PARK2 and PARK6, ...encoding the E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, account for a large proportion of cases of autosomal recessive early‐onset PD. PINK1 and Parkin regulate mitochondrial quality control and have been linked to the modulation of innate immunity pathways. We report here an exacerbation of NLRP3 inflammasome activation by specific inducers in microglia and bone marrow‐derived macrophages from Park2−/− and Pink1−/− mice. The caspase 1‐dependent release of IL‐1β and IL‐18 was, therefore, enhanced in Park2−/− and Pink1−/− cells. This defect was confirmed in blood‐derived macrophages from patients with PARK2 mutations and was reversed by MCC950, which specifically inhibits NLRP3 inflammasome complex formation. Enhanced NLRP3 signaling in Parkin‐deficient cells was accompanied by a lack of induction of A20, a well‐known negative regulator of the NF‐κB pathway recently shown to attenuate NLRP3 inflammasome activity. We also found an inverse correlation between A20 abundance and IL‐1β release, in human macrophages challenged with NLRP3 inflammasome inducers. Overall, our observations suggest that the A20/NLRP3‐inflammasome axis participates in the pathogenesis of PARK2‐linked PD, paving the way for the exploration of its potential as a biomarker and treatment target.
Main Points
Parkin deficiency exacerbates the NLRP3 inflammasome by disrupting A20‐dependent negative regulation.
NLRP3 inflammasome overactivation and A20 deregulation were also observed in blood‐derived macrophages from patients with PARK2 mutations.
Abstract Mutations in SPG11 account for the most common form of autosomal recessive hereditary spastic paraplegia (HSP), characterized by a gait disorder associated with various brain alterations. ...Mutations in the same gene are also responsible for rare forms of Charcot-Marie-Tooth (CMT) disease and progressive juvenile-onset amyotrophic lateral sclerosis (ALS). To elucidate the physiopathological mechanisms underlying these human pathologies, we disrupted the Spg11 gene in mice by inserting stop codons in exon 32, mimicking the most frequent mutations found in patients. The Spg11 knockout mouse developed early-onset motor impairment and cognitive deficits. These behavioral deficits were associated with progressive brain atrophy with the loss of neurons in the primary motor cortex, cerebellum and hippocampus, as well as with accumulation of dystrophic axons in the corticospinal tract. Spinal motor neurons also degenerated and this was accompanied by fragmentation of neuromuscular junctions and muscle atrophy. This new Spg11 knockout mouse therefore recapitulates the full range of symptoms associated with SPG11 mutations observed in HSP, ALS and CMT patients. Examination of the cellular alterations observed in this model suggests that the loss of spatacsin leads to the accumulation of lipids in lysosomes by perturbing their clearance from these organelles. Altogether, our results link lysosomal dysfunction and lipid metabolism to neurodegeneration and pinpoint a critical role of spatacsin in lipid turnover.
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.
Chronic alpha-synuclein (
) overexpression is a relatively homogenous and well-defined cause of parkinsonism and dementia. Parkinson's disease (PD), PD with dementia, dementia with Lewy bodies and ...multiple system atrophy all manifest in
multiplication families. Herein we summarize genealogic, clinical and genetic data from 59 families (25 not previously published) with parkinsonism caused by
multiplications. Longitudinal clinical assessments and genealogic relationships were documented for all family members. All probands were genotyped with an Illumina MEGA high-density genotyping array to identify copy number variants (CNV) and enable
multiplication breakpoints to be defined. Three
short tandem repeat (STR) markers were genotyped in all available samples to validate genomic dosage and inheritance. A web-application was built as a forum for future data sharing. CNV analysis identified 49 subjects with heterozygous
duplication (CNV3), 2 with homozygous duplication (CNV4) and 7 with a triplication mutation (CNV4). Clinical presentations varied greatly throughout the cohort.
dosage correlates with disease onset (mean age of onset CNV3: 46.9 ± 10.5 years vs. 34.5 ± 7.4 CNV4,
= 0.003). Atypical or more severe clinical courses were described in several patients and dementia was noted in 50.9% of the probands. Neither the multiplication size (average 2.05 ± 2.45 Mb) nor the number of genes included (range 1-50) was associated with motor symptom onset or dementia. Families with
multiplication are rare and globally-distributed. Nevertheless, they may both inform and benefit from the development of
targeted therapeutic strategies relevant to the treatment of all alpha-synucleinopathies.
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