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Synucleinopathies are mostly sporadic neurodegenerative disorders of partly unexplained aetiology, and include Parkinson's disease (PD) and multiple system atrophy (MSA). We have further investigated our recent finding of somatic SNCA (α-synuclein) copy number variants (CNVs, specifically gains) in synucleinopathies, using Fluorescent in-situ Hybridisation for SNCA, and single-cell whole genome sequencing for the first time in a synucleinopathy. In the cingulate cortex, mosaicism levels for SNCA gains were higher in MSA and PD than controls in neurons (> 2% in both diseases), and for MSA also in non-neurons. In MSA substantia nigra (SN), we noted SNCA gains in > 3% of dopaminergic (DA) neurons (identified by neuromelanin) and neuromelanin-negative cells, including olig2-positive oligodendroglia. Cells with CNVs were more likely to have α-synuclein inclusions, in a pattern corresponding to cell categories mostly relevant to the disease: DA neurons in Lewy-body cases, and other cells in the striatonigral degeneration-dominant MSA variant (MSA-SND). Higher mosaicism levels in SN neuromelanin-negative cells may correlate with younger onset in typical MSA-SND, and in cingulate neurons with younger death in PD. Larger sample sizes will, however, be required to confirm these putative findings. We obtained genome-wide somatic CNV profiles from 169 cells from the substantia nigra of two MSA cases, and pons and putamen of one. These showed somatic CNVs in ~ 30% of cells, with clonality and origins in segmental duplications for some. CNVs had distinct profiles based on cell type, with neurons having a mix of gains and losses, and other cells having almost exclusively gains, although control data sets will be required to determine possible disease relevance. We propose that somatic SNCA CNVs may contribute to the aetiology and pathogenesis of synucleinopathies, and that genome-wide somatic CNVs in MSA brain merit further study.

Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.

ObjectiveTo identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS).MethodsWe performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed.ResultsWe found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10-6, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA.ConclusionsWe present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps.

Background: The objective of this study was to evaluate whether the levels of coenzyme Q10 (CoQ10) in brain tissue of multiple system atrophy (MSA) patients differ from those in elderly controls and in patients with other neurodegenerative diseases. Methods: Flash frozen brain tissue of a series of 20 pathologically confirmed MSA patients [9 olivopontocerebellar atrophy (OPCA) type, 6 striatonigral degeneration (SND) type, and 5 mixed type] was used for this study. Elderly controls (n = 37) as well as idiopathic Parkinson's disease (n = 7), dementia with Lewy bodies (n = 20), corticobasal degeneration (n = 15) and cerebellar ataxia (n = 18) patients were used as comparison groups. CoQ10 was measured in cerebellar and frontal cortex tissue by high performance liquid chromatography. Results: We detected a statistically significant decrease (by 3–5%) in the level of CoQ10 in the cerebellum of MSA cases (P = 0.001), specifically in OPCA (P = 0.001) and mixed cases (P = 0.005), when compared to controls as well as to other neurodegenerative diseases [dementia with Lewy bodies (P<0.001), idiopathic Parkinson's disease (P<0.001), corticobasal degeneration (P<0.001), and cerebellar ataxia (P = 0.001)]. Conclusion: Our results suggest that a perturbation in the CoQ10 biosynthetic pathway is associated with the pathogenesis of MSA but the mechanism behind this finding remains to be elucidated. [ABSTRACT FROM AUTHOR]