title: DJ-1 linked parkinsonism (PARK7) is associated with Lewy body pathology.
abstract: Mutations in DJ-1 (encoded by PARK7) are a very rare cause of early-onset recessive Parkinson's disease. We describe a patient with early-onset parkinsonism, starting at the age of 22, with poor response to levodopa and additional features in progression (dystonia, pyramidal signs and dementia), who died when he was 49 years old. The neuropathological study showed severe substantia nigra and locus coeruleus neuronal loss, with diffuse Lewy body pathology (Lewy bodies, aberrant neurites, grain-like structures, spheroids and scattered glial pathology). Genetic analysis revealed a novel c.515T > A; p.L172Q mutation in the PARK7 gene. To evaluate the pathogenicity of this new mutation we explored DJ-1 expression levels in vitro showing a massive reduction in DJ-1 protein levels due to a highly unstable and rapidly degraded L172Q mutant. DJ-1 immunohistochemistry of brain tissue revealed no staining in our case. This is the first neuropathological report of a brain from DJ-1-linked parkinsonism that, although based on a single case study, suggests that DJ-1 mutations are causative of α-synucleinopathy. These results can help in the understanding of Parkinson's disease pathophysiology, promote research studies to increase the knowledge on the pathways involved in the neurodegeneration process, and pave the way for new therapeutic interventions.
authors.affiliation: Portuguese Brain Bank, Neuropathology Unit, Centro Hospitalar do Porto, Porto, Portugal ricardotaipa@gmail.com rtaipa.neuropat@chporto.min-saude.pt.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Taipa
authors.affiliation: UnIGENe, IBMC, Institute for Molecular and Cell Biology, and Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.
authors.forename: Conceição
authors.initials: C
authors.lastname: Pereira
authors.affiliation: Portuguese Brain Bank, Neuropathology Unit, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Reis
authors.affiliation: UnIGENe, IBMC, Institute for Molecular and Cell Biology, and Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Alonso
authors.affiliation: Department of Neurology, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Bastos-Lima
authors.affiliation: Portuguese Brain Bank, Neuropathology Unit, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Manuel
authors.initials: M
authors.lastname: Melo-Pires
authors.affiliation: Department of Neurology, Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Marina
authors.initials: M
authors.lastname: Magalhães
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016631:Lewy Bodies / Q000473:pathology*; D008125:Locus Coeruleus / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009410:Nerve Degeneration / Q000150:complications / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology*; D000071617:Protein Deglycase DJ-1 / Q000096:biosynthesis / Q000235:genetics*; D013378:Substantia Nigra / Q000473:pathology*
chemical_list: D000071617:Protein Deglycase DJ-1
keywords: DJ-1; Lewy body; PARK7; pathology; α-synuclein