Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

Abstract

Lysosomal storage disorders comprise a clinically heterogeneous group of autosomal-recessive or X-linked genetic syndromes caused by disruption of lysosomal biogenesis or function resulting in accumulation of nondegraded substrates. Although lysosomal storage disorders are diagnosed predominantly in children, many show variable expressivity with clinical presentations possible later in life. Given the important role of lysosomes in neuronal homeostasis, neurological manifestations, including movement disorders, can accompany many lysosomal storage disorders. Over the last decade, evidence from genetics, clinical epidemiology, cell biology, and biochemistry have converged to implicate links between lysosomal storage disorders and adult-onset movement disorders. The strongest evidence comes from mutations in Glucocerebrosidase, which cause Gaucher's disease and are among the most common and potent risk factors for PD. However, recently, many additional lysosomal storage disorder genes have been similarly implicated, including SMPD1, ATP13A2, GALC, and others. Examination of these links can offer insight into pathogenesis of PD and guide development of new therapeutic strategies. We systematically review the emerging genetic links between lysosomal storage disorders and PD. © 2019 International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; genetics; lysosomal storage disease; movement disorders.

Figure 1.

LSD genes important in ceramide metabolism are also implicated in PD. Mutations in GBA1, SMPD1, and GALC are responsible for Gaucher disease, Niemann-Pick disease type A and B, and Krabbe disease, respectively. GBA1 encodes for GCase which hydrolyzes glucosylceramide to glucose and ceramide, SMPD1 encodes for acid sphingomyelinase which hydrolyzes sphingomyelin to phosphocholine and ceramide, GALC encodes for galactosidase which hydrolyzes galactosyl moieties from lipids including the hydrolysis of galactosylceramide to galactose and ceramide.

Figure 2.

A hypothetical model for oligogenic risk in PD. Genetic mutations associated with LSDs cause severe impairment in lysosomal function resulting in significant lipid accumulations and leading to the severe phenotypes observed in juvenile onset LSDs. In cases where mutations result in modest impairments that are associated with PD, lysosomal function is maintained to an extent where lipid metabolism can be relatively normal. However, mild impairments in overall lysosomal protein degradation efficiency caused by one or more LSD genetic variants in combination other genetic and/or non-genetic risk factors as well as aging may further disrupt cellular proteostasis, leading to accumulation of alpha synuclein and ultimately, PD.