Is there a link between autophagy, sarcoidosis, and non granulomatous neurological disorders?

Abstract

Introduction: Previous genomic studies suggested that impaired autophagy could promote sarcoidosis (Pacheco et al. Trends Immunol 2020; 41: 286–299). Autophagy can be altered in nongranulomatous neurological disorders (NGND) such as frontotemporal dementia (FTD) or Parkinson’s disease (PD) in which the accumulation of proteins such as α-synuclein due to an mitophagy defect had been suggested.

Methods: We performed a whole exome sequencing (WES) study of sarcoidosic patients in the SARCFAM (familial sarcoidosis) cohort (familial sarcoidosis). In order to distinguish potentially pathogenic variants, a genomic subtraction with internal controls among siblings in each family was performed.

Results: We focused on seven patients with NGND and sarcoidosis association out of the SARCFAM cohort (Calender et al. Eur Respir J 2019; 54). Patients were experiencing various NGND such as neurodegenerative (FTD, PD) or inflammatory disorders (encephalomyelitis). Accumulation of rare (minor allele frequency < 0.01) pathogenic variants (SIFT score < 0.400, Polyphenv2 score < 0.05) were found in genes involved in mitophagy, interleukin-17 signaling, Ras signaling, lysosomal and autophagy pathways (respective OR=33.28, 23.01, 14.37, 17.28 and 16.59, p<0.05) according to the Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis. Several genes (LRRK2, PARK7, DDIT4) are also suspected to have a role in PD.

Conclusion: These data suggest that sarcoidosis and NGND are at a crossroads of auto/mitophagy dysregulation and that the accumulation of pathogenic variants could promote both diseases.