PT  - JOURNAL ARTICLE
AU  - Christopher Hatton
AU  - Simona S. Ghanem
AU  - David J. Koss
AU  - Ilham Y. Abdi
AU  - Elizabeth Gibbons
AU  - Rita Guerreiro
AU  - Jose Bras
AU  - International DLB Genetics Consortium
AU  - Lauren Walker
AU  - Ellen Gelpi
AU  - Wendy Heywood
AU  - Tiago F. Outeiro
AU  - Johannes Attems
AU  - Bobby McFarland
AU  - Rob Forsyth
AU  - Omar M. El-Agnaf
AU  - Daniel Erskine
TI  - Prion-like α-synuclein pathology in the brains of infants: Krabbe disease as a novel seed-competent α-synucleinopathy
AID  - 10.1101/2021.10.12.463948
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.10.12.463948
4099  - http://biorxiv.org/content/early/2021/10/14/2021.10.12.463948.short
4100  - http://biorxiv.org/content/early/2021/10/14/2021.10.12.463948.full
AB  - Krabbe disease (KD) is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene which causes accumulation of the toxic sphingolipid psychosine. GALC variants are associated with increased risk of Lewy body diseases (LBD), an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in KD has pathological similarities to that in LBD, we compared post-mortem KD tissue to that of infant control cases and identified alterations to α-synuclein localisation and expression of modifications associated with LBD. To determine whether α-synuclein in KD displayed pathogenic properties associated with LBD we evaluated its seeding capacity using the real-time quaking-induced conversion assay. Strikingly, seeded aggregation of α-synuclein resulted in the formation of fibrillar aggregates similar to those observed in LBD, confirming the prion-like capacity of KD-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it can result from alterations to biological processes such as sphingolipid homeostasis. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in LBD.Competing Interest StatementThe authors have declared no competing interest.