The role of monogenic genes in idiopathic Parkinson’s disease

Abstract

In the past two decades, mutations in multiple genes have been linked to autosomal dominant or recessive forms of monogenic Parkinson's disease (PD). Collectively, these monogenic (often familial) cases account for less than 5% of all PD, the majority being apparently sporadic cases. More recently, large-scale genome-wide association studies have identified over 40 loci that increase risk of PD. Importantly, there is overlap between monogenic and sporadic PD genes, particularly for the loci that contain the genes SNCA and LRRK2, which are mutated in monogenic dominant PD. There have also been reports of idiopathic PD cases with heterozygous variants in autosomal recessive genes suggesting that these mutations may increase risk of PD. These observations suggest that monogenic and idiopathic PD may have shared pathogenic mechanisms. Here, we focus mainly on the role of monogenic PD genes that represent pleomorphic risk loci for idiopathic PD. We also discuss the functional mechanisms that may play a role in increasing risk of disease in both monogenic and idiopathic forms.

Ethnic Variation in the Manifestation of Parkinson’s Disease: A Narrative Review

“…The commonest monogenic forms of PD are caused by mutations in genes such as LRRK2, PARK2, SNCA and DJ-1 [123]. They are associated with different phenotypes and their prevalence differs in different ethnic groups [124,125].…”

Vesicular Dysfunction and the Pathogenesis of Parkinson’s Disease: Clues From Genetic Studies

“…Existing therapies are palliative in nature, with dopamine replacement as the main treatment strategy -an approach that does not halt or prevent disease progression. With regard to the underlying etiology, the majority of Parkinson's cases are idiopathic with no discernible specific environmental or genetic cause, however, approximately 5-10% of cases are linked directly to deleterious inherited genetic variants (Reed et al, 2019). Over the past two decades mutations in at least 17 disease segregating genes have been identified [reviewed in Karimi-Moghadam et al (2018)].…”

Autophagy and LRRK2 in the Aging Brain

“…LRRK2 mutations are the most common genetic cause of familial PD (Zimprich et al, 2004;Paisan-Ruiz et al, 2005) and GWAS studies revealed LRRK2 represents a risk factor for idiopathic PD (Nalls et al, 2014). At least six pathogenic mutations of LRRK2 have been identified: two in the kinase domain (G2019S and I2020T), three (R1441C/G/H) in the GTPase/ROC domain, and one (Y1669C) in the CoR domain (Reed et al, 2019). The G2019S mutation is most frequently associated with PD, followed by R1441C/G/H (Gasser, 2009;Okubadejo et al, 2018).…”