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Emerging links between pediatric lysosomal storage diseases and adult parkinsonism
Daniel Ysselstein1, Joshua M Shulman2,3, Dimitri Krainc1
1Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Insights
Lysosomal storage disorders are linked to adult-onset movement disorders, including Parkinson's disease (PD). Genetic mutations causing these disorders are increasingly recognized as risk factors for PD, offering new therapeutic insights.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Lysosomal storage disorders (LSDs) are genetic conditions causing substrate accumulation due to impaired lysosomal function.
- While often diagnosed in childhood, LSDs can manifest later in life with neurological symptoms, including movement disorders.
- Lysosomes play a crucial role in neuronal health, and their dysfunction is implicated in neurodegenerative diseases.
Purpose of the Study:
- To systematically review the emerging genetic links between lysosomal storage disorders and Parkinson's disease (PD).
- To explore how understanding these links can provide insights into PD pathogenesis.
- To guide the development of novel therapeutic strategies for PD.
Main Methods:
- Systematic review of genetic, epidemiological, cell biology, and biochemical evidence.
- Analysis of implicated lysosomal storage disorder genes and their association with movement disorders.
- Examination of established and newly identified genetic risk factors for PD.
Main Results:
- Mutations in Glucocerebrosidase (GBA), causing Gaucher's disease, are a significant risk factor for PD.
- Several other LSD genes, including SMPD1 and ATP13A2, are increasingly implicated in PD.
- Evidence converges from multiple scientific disciplines to support the LSD-PD connection.
Conclusions:
- Lysosomal dysfunction is a key factor in the pathogenesis of certain adult-onset movement disorders, particularly PD.
- Identifying genetic links between LSDs and PD opens avenues for understanding disease mechanisms.
- This research highlights potential targets for developing new PD therapies.
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.
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