Early-onset Dementia with Lewy Bodies

The clinical and neuropathological characteristics of an atypical form of dementia with Lewy bodies (DLB) are described. The proband experienced difficulties in her school performance at 13 years of age. Neurological examination revealed cognitive dysfunction, dysarthria, parkinsonism and myoclonus. By age 14 years, the symptoms had worsened markedly and the proband died at age 15 years. On neuropathological examination, the brain was severely atrophic. Numerous intracytoplasmic and intraneuritic Lewy bodies, as well as Lewy neurites, were present throughout the cerebral cortex and subcortical nuclel; vacuolar changes were seen in the upper layers of the neocortex and severe neuronal loss and gliosis were evident in the cerebral cortex and substantia nigra. Lewy bodies and Lewy neurites were strongly immunoreactive for alpha-synuclein and ubiquitin. Lewy bodies were composed of filamentous and granular material and isolated filaments were decorated by alpha-synuclein antibodies. Immunohistochemistry for tau or beta-amyloid yielded negative results. The etiology of this atypical form of DLB is unknown, since there was no family history and since sequencing of the exonic regions of alpha-Synuclein, beta-Synuclein, Synphilin-1, Parkin, Ubiquitin C-terminal hydrolase L1 and Neurofilament-M failed to reveal a pathogenic mutation. This study provides further evidence of the clinical and pathological heterogeneity of DLB

New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy.

Acknowledgements: This work was supported by the Electron Microscopy Facility of the MRC Laboratory of Molecular Biology. We thank Jake Grimmett, Toby Darling and Ivan Clayson for help with high-performance computing, and Rose Richardson and Max Jacobsen for help with neuropathology. We acknowledge Diamond Light Source for access and support of the cryo-EM facilities at the UK’s Electron Bio-Imaging Centre (under proposal bi23268), funded by the Wellcome Trust, the MRC and the Biotechnology and Biological Sciences Research Council (BBSRC). M.G. is an Associate Member of the UK Dementia Research Institute. For the purpose of open access, the MRC Laboratory of Molecular Biology has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising.A 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This mutation translates into the insertion of MAAAEKT after residue 22 of α-synuclein, resulting in a protein of 147 amino acids. Both wild-type and mutant proteins were present in sarkosyl-insoluble material that was extracted from frontal cortex of the individual with JOS and examined by electron cryo-microscopy. The structures of JOS filaments, comprising either a single protofilament, or a pair of protofilaments, revealed a new α-synuclein fold that differs from the folds of Lewy body diseases and multiple system atrophy (MSA). The JOS fold consists of a compact core, the sequence of which (residues 36-100 of wild-type α-synuclein) is unaffected by the mutation, and two disconnected density islands (A and B) of mixed sequences. There is a non-proteinaceous cofactor bound between the core and island A. The JOS fold resembles the common substructure of MSA Type I and Type II dimeric filaments, with its core segment approximating the C-terminal body of MSA protofilaments B and its islands mimicking the N-terminal arm of MSA protofilaments A. The partial similarity of JOS and MSA folds extends to the locations of their cofactor-binding sites. In vitro assembly of recombinant wild-type α-synuclein, its insertion mutant and their mixture yielded structures that were distinct from those of JOS filaments. Our findings provide insight into a possible mechanism of JOS fibrillation in which mutant α-synuclein of 147 amino acids forms a nucleus with the JOS fold, around which wild-type and mutant proteins assemble during elongation