Rare genetic variants support mitochondrial dysfunction in Lewy body disorders

Parkinson disease (PD) and other Lewy body disorders are common neurodegenerative conditions manifesting with progressive motor and nonmotor symptoms. Although their pathogenesis remains to be fully elucidated, a number of genetic findings have helped better understand the molecular mechanisms involved.¹ Mutations in genes causing PD that are inherited in a Mendelian fashion as well as genetic variants that modify disease risk have been identified, some overlapping with those involved in other Lewy body disorders. Recently, mutations in a gene named coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) were found in Japanese patients from families with autosomal dominantly inherited PD.² Moreover, a patient-control analysis suggested that variants in CHCHD2 associate with increased risk for sporadic, late-onset PD.² These findings have raised strong interest given that (1) the CHCHD2 protein is localized in mitochondria and (2) mitochondrial dysfunction plays an important role in PD, particularly early-onset PD due to mutations in PINK1 and PARKIN.³