Targeting neurological abnormalities in lysosomal storage diseases. (June 2022)

• Record Type: Journal Article
• Authors: van Gool, Raquel; Tucker-Bartley, Anthony; Yang, Edward; Todd, Nicholas; Guenther, Frank; Goodlett, Benjamin; Al-Hertani, Walla; Bodamer, Olaf A.; Upadhyay, Jaymin
• Is Part Of: Trends in pharmacological sciences. Volume 43:Number 6(2022)
• Page Start: 495
• Page End: 509
• Publication Date: 2022-06
• Subjects: lysosomal storage disease -- autophagy -- central nervous system abnormalities -- neurological symptoms -- psychiatric symptoms; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2021.11.005
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : Central nervous system (CNS) abnormalities and corresponding neurological and psychiatric symptoms are frequently observed in lysosomal storage disorders (LSDs). The genetic background of individual LSDs is indeed unique to each illness. However, resulting defective lysosomal function within the CNS can transition normal cellular processes (i.e., autophagy) into aberrant mechanisms, facilitating overlapping downstream consequences including neurocircuitry dysfunction, neurodegeneration as well as sensory, motor, cognitive, and psychological symptoms. Here, the neurological and biobehavioral phenotypes of major classes of LSDs are discussed alongside therapeutic strategies in development that aim to tackle neuropathology among other disease elements. Finally, focused ultrasound blood–brain barrier opening is proposed to enhance therapeutic delivery thereby overcoming the key hurdle of central distribution of disease modifying therapies in LSDs. Highlights: Defective lysosomal function facilitates aberrant autophagic processes as well as a number of downstream central nervous system (CNS) abnormalities and clinical symptoms in lysosomal storage disorders (LSDs). While approved treatments have had a major impact for many LSDs, mitigation of neuropathology and the associated symptoms remain critical unmet needs. Addressing compromised autophagy and treatment of neuropathology in LSDs serves as the key focus for many therapeutics in development with targeted and safe central delivery representing a universal hurdle. Overlapping and aberrant molecular, functional, and structural properties localized to cortico-thalamo-striatal-cerebellar circuitry may help explain phenotypic and symptomatic similarities observed across LSDs, and additionally, may serve as novel CNS biomarkers. Focused ultrasound-guided blood-brain barrier permeabilization may play a key role in the targeted delivery of disease modifying therapeutics to the CNS across LSDs.