Large-scale mitochondrial DNA deletion underlying familial multiple system atrophy of the cerebellar subtype.
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ABSTRACT:
SUBMITTER: Alsemari A
PROVIDER: S-EPMC4736521 | biostudies-other | 2016 Feb
REPOSITORIES: biostudies-other
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Project description:AimsRecently, mutations in COQ2 encoding para-hydroxybenzoate-polyprenyl transferase have been identified to increase the risk of multiple system atrophy (MSA) in multiplex families and sporadic cases. The prevalence of COQ2 mutations was showed to be higher in cerebellar subtype (MSA-C) than parkinsonism subtype (MSA-P). The aim of this study was to investigate the association between COQ2 mutations and MSA-C in Chinese patients.MethodsA Chinese cohort of 116 patients with MSA-C and 192 healthy control individuals were recruited. Sanger sequencing of COQ2 was performed in all these subjects.ResultsTwo missense mutations (p.L402F and p.R173H) and one synonymous mutation (p.A32A) were detected in 3 patients, respectively. They were not found in the 192 controls as well as the 1000 Genomes Database. The p.L402F and p.A32A were novel.ConclusionOur results indicated that COQ2 tended to play a population-specific and subtype-depended role in conferring susceptibility to MSA.
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Project description:ObjectiveSingle, large-scale deletions in mitochondrial DNA (mtDNA) are a common cause of mitochondrial disease. This study aimed to investigate the relationship between the genetic defect and molecular phenotype to improve understanding of pathogenic mechanisms associated with single, large-scale mtDNA deletions in skeletal muscle.MethodsWe investigated 23 muscle biopsies taken from adult patients (6 males/17 females with a mean age of 43 years) with characterized single, large-scale mtDNA deletions. Mitochondrial respiratory chain deficiency in skeletal muscle biopsies was quantified by immunoreactivity levels for complex I and complex IV proteins. Single muscle fibers with varying degrees of deficiency were selected from 6 patient biopsies for determination of mtDNA deletion level and copy number by quantitative polymerase chain reaction.ResultsWe have defined 3 "classes" of single, large-scale deletion with distinct patterns of mitochondrial deficiency, determined by the size and location of the deletion. Single fiber analyses showed that fibers with greater respiratory chain deficiency harbored higher levels of mtDNA deletion with an increase in total mtDNA copy number. For the first time, we have demonstrated that threshold levels for complex I and complex IV deficiency differ based on deletion class.InterpretationCombining genetic and immunofluorescent assays, we conclude that thresholds for complex I and complex IV deficiency are modulated by the deletion of complex-specific protein-encoding genes. Furthermore, removal of mt-tRNA genes impacts specific complexes only at high deletion levels, when complex-specific protein-encoding genes remain. These novel findings provide valuable insight into the pathogenic mechanisms associated with these mutations. Ann Neurol 2018;83:115-130.
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Project description:Multiple system atrophy (MSA) is a rare, but fatal atypical parkinsonian disorder. The prototypical pathological hallmark are oligodendroglial cytoplasmic inclusions (GCIs) containing alpha-synuclein (α-syn). Currently, two MSA phenotypes are classified: the parkinsonian (MSA-P) and the cerebellar subtype (MSA-C), clinically characterized by predominant parkinsonism or cerebellar ataxia, respectively. Previous studies have shown that the transgenic MSA mouse model overexpressing human α-syn controlled by the oligodendroglial myelin basic protein (MBP) promoter (MBP29-hα-syn mice) mirrors crucial characteristics of the MSA-P subtype. However, it remains elusive, whether this model recapitulates important features of the MSA-C-related phenotype. First, we examined MSA-C-associated cerebellar pathology using human post-mortem tissue of MSA-C patients and controls. We observed the prototypical GCI pathology and a preserved number of oligodendrocytes in the cerebellar white matter (cbw) accompanied by severe myelin deficit, microgliosis, and a profound loss of Purkinje cells. Secondly, we phenotypically characterized MBP29-hα-syn mice using a dual approach: structural analysis of the hindbrain and functional assessment of gait. Matching the neuropathological features of MSA-C, GCI pathology within the cbw of MBP29-hα-syn mice was accompanied by a severe myelin deficit despite an increased number of oligodendrocytes and a high number of myeloid cells even at an early disease stage. Intriguingly, MBP29-hα-syn mice developed a significant loss of Purkinje cells at a more advanced disease stage. Catwalk XT gait analysis revealed decreased walking speed, increased stride length and width between hind paws. In addition, less dual diagonal support was observed toward more dual lateral and three paw support. Taken together, this wide-based and unsteady gait reflects cerebellar ataxia presumably linked to the cerebellar pathology in MBP29-hα-syn mice. In conclusion, the present study strongly supports the notion that the MBP29-hα-syn mouse model mimics important characteristics of the MSA-C subtype providing a powerful preclinical tool for evaluating future interventional strategies.
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Project description:ObjectiveNeuroanatomical differences in the cerebellum are among the most consistent findings in multiple system atrophy (MSA) patients. This study performed a detailed cerebellar morphology in MSA patients and its two subtypes: MSA-P (parkinson's symptoms predominate) and MSA-C (cerebellar symptoms predominant), and their relations to profiles of motor and cognitive deficits.Materials and methodsStructure MRI data were acquired from 63 healthy controls and 61 MSA patients; voxel-based morphometry and the Spatially Unbiased Infratentorial Toolbox cerebellar atlas were performed to identify the cerebellar gray volume changes in MSA and its subtypes. Further, the gray matter changes were correlated with the clinical motor/cognitive scores.ResultsPatients with MSA exhibited widespread loss of cerebellar volume bilaterally, relative to healthy controls. In those with MSA-C, gray matter loss was detected from anterior (bilateral lobule IV-V) to posterior (bilateral crus I/II, bilateral lobule IX, left lobule VIII) cerebellar lobes. Lower anterior cerebellar volume negatively correlated with disease duration and motor performance, whereas posterior lobe integrity positively correlated with cognitive assessment. In patients with MSA-P, atrophy of anterior lobe (bilateral lobules IV-V) and posterior lobe in part (left lobule VI, bilateral IX) was evident; and in left cerebellar lobule IX, gray matter loss negatively correlated with motor scores. Direct comparison of MSA-P and MSA-C group outcomes showed divergence in right cerebellar crus II only.ConclusionsOur data suggest that volumetric abnormalities of cerebellum contribute substantially to motor and cognitive performance in patients with MSA. In patients with MSA-P and MSA-C, affected regions of cerebellum differed.
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Project description:In the neurodegenerative disease multiple system atrophy (MSA), ?-synuclein misfolds into a self-templating conformation to become a prion. To compare the biological activity of ?-synuclein prions in MSA and Parkinson's disease (PD), we developed nine ?-synuclein-YFP cell lines expressing point mutations responsible for inherited PD. MSA prions robustly infected wild-type, A30P, and A53T ?-synuclein-YFP cells, but they were unable to replicate in cells expressing the E46K mutation. Coexpression of the A53T and E46K mutations was unable to rescue MSA prion infection in vitro, establishing that MSA ?-synuclein prions are conformationally distinct from the misfolded ?-synuclein in PD patients. This observation may have profound implications for developing treatments for neurodegenerative diseases.
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Project description:We investigated a hereditary cerebellar ataxia in Belgian Shepherd dogs. Affected dogs developed uncoordinated movements and intention tremor at two weeks of age. The severity of clinical signs was highly variable. Histopathology demonstrated atrophy of the CNS, particularly in the cerebellum. Combined linkage and homozygosity mapping in a family with four affected puppies delineated a 52 Mb critical interval. The comparison of whole genome sequence data of one affected dog to 735 control genomes revealed a private homozygous structural variant in the critical interval, Chr4:66,946,539_66,963,863del17,325. This deletion includes the entire protein coding sequence of SELENOP and is predicted to result in complete absence of the encoded selenoprotein P required for selenium transport into the CNS. Genotypes at the deletion showed the expected co-segregation with the phenotype in the investigated family. Total selenium levels in the blood of homozygous mutant puppies of the investigated litter were reduced to about 30% of the value of a homozygous wildtype littermate. Genotyping >600 Belgian Shepherd dogs revealed an additional homozygous mutant dog. This dog also suffered from pronounced ataxia, but reached an age of 10 years. Selenop-/- knock-out mice were reported to develop ataxia, but their histopathological changes were less severe than in the investigated dogs. Our results demonstrate that deletion of the SELENOP gene in dogs cause a defect in selenium transport associated with CNS atrophy and cerebellar ataxia (CACA). The affected dogs represent a valuable spontaneous animal model to gain further insights into the pathophysiological consequences of CNS selenium deficiency.
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